Methods and compositions for inhibiting the interaction of menin with MLL proteins

ABSTRACT

The present disclosure provides compositions and methods of use to inhibit the interaction of menin with MLL1, MLL2 and MLL-fusion oncoproteins. The compositions and methods of use are useful for the treatment of leukemia, solid cancers, diabetes and other diseases dependent on activity of MLL1, MLL2, MLL fusion proteins, and/or menin.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application No.62/517,041, filed Jun. 8, 2017 and U.S. Provisional Application No.62/636,976, filed Mar. 1, 2018, each incorporated herein by reference inits entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on May 21, 2018, isnamed 47535721601_SL.txt and is 15,910 bytes in size.

BACKGROUND OF THE INVENTION

The mixed-lineage leukemia (MLL) protein is a histone methyltransferasecritical for the epigenetic regulation of gene transcription. Many acuteleukemias, including acute myeloblastic leukemia (AML), acutelymphoblastic leukemia (ALL) and mixed-lineage leukemia (MLL), arecharacterized by the presence of chimeric MLL fusion proteins thatresult from chromosomal translocations of the MLL gene located atchromosome 11, band q23 (11q23). Chimeric MLL fusion proteins retainapproximately 1,400 amino acids of the N-terminus of MLL, but are fusedwith one of approximately 80 partner proteins (e.g., AF4, AF9, ENL,AF10, ELL, AF6, AF1p, GAS7). MLL fusion proteins lack the originalhistone methyltransferase activity of the C-terminus of MLL and gain theability to regulate transcription of numerous oncogenes, including HOXand MEIS1, resulting in increased cell proliferation and decreased celldifferentiation, ultimately leading to leukemogenesis.

The menin protein, which is encoded by the Multiple Endocrine Neoplasia(MEN) gene, is a ubiquitously expressed nuclear protein that engages ininteractions with DNA processing and repair proteins, chromatinmodifying proteins and numerous transcription factors (Agarwal, et al.;Horm Metab Res, 2005, 37(6): 369-374). The association of menin with theN-terminus of MLL fusion proteins is necessary for the observedoncogenic activity of MLL fusion proteins. This association has beenshown to constitutively up-regulate the expression of HOX and MEIS1oncogenes and impairs proliferation and differentiation of hematopoieticcells leading to leukemia development. Since menin has been shown tofunction as a general oncogenic cofactor in MLL-related leukemias, theinteraction between menin and MLL fusion proteins and MLL represents apotential chemotherapeutic target.

Patients, especially infants, with leukemias harboring chromosomaltranslocations of the MLL gene have a dismal prognosis, with less than a40% five year survival rate (Slany; Haematologica, 2009, 94(7):984-993). A novel therapeutic strategy is urgently needed to treat theseleukemias. Small molecule inhibitors that block the menin-MLLinteraction are thus valuable targets for treating diseases involvingthe MLL fusion proteins.

SUMMARY OF THE INVENTION

The present disclosure addresses a need in the art by providingcompositions and methods for inhibiting the protein-protein interactionof menin with MLL1, MLL2 and MLL-fusion oncoproteins. The compositionsand methods herein may be useful for treating diseases dependent on theactivity of MLL1, MLL2, MLL fusion proteins, and/or menin such asleukemia, solid cancers, and diabetes. In certain embodiments, acompound of the disclosure interacts non-covalently with menin andinhibits the interaction of menin with MLL. In certain embodiments, acompound of the disclosure covalently binds menin and inhibits theinteraction of menin with MLL.

In some embodiments of a compound provided herein, the compoundnon-covalently or covalently binds to any one or more isoforms of menin,for example, isoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2) orisoform 3 (SEQ ID NO: 3) of menin. In certain embodiments, the meninprotein shares 60% or more, 70% or more, 75% or more, 80% or more, 85%or more, 90% or more, 95% or more, or 99% or more sequence identity withisoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2) or isoform 3 (SEQ IDNO: 3).

In one aspect, the present disclosure provides a compound of FormulaVIII:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   H-VIII is selected from an optionally substituted 5-membered        heteroaryl, an optionally substituted 6-membered aryl, and an        optionally substituted 6-membered heteroaryl,    -   wherein ring carbons of H-VIII are, at each occurrence,        independently optionally substituted with R², R¹⁴, or R¹⁶ and        ring nitrogens of H-VIII are, at each occurrence, independently        optionally substituted with R¹⁵    -   each of L¹ and L² is independently a bond, carbonyl, O, S,        —NR⁵—, —NR⁶CH₂—, —NR⁶C(═O)—, —NR⁶SO₂—, alkylene, alkenylene,        heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl, or        heteroalkylenecarbonyl;    -   A is a bond, a 3-7 membered saturated ring, or a 3-7 membered        unsaturated ring;    -   m is an integer from 0 to 12;    -   B is selected from B-I, B-II, B-III, and B-IV,    -   wherein B is connected at any ring atom to L²;    -   B-I is

-   -   B-II is

-   -   B-III is

-   -   B-IV is

-   -   each of Z¹, Z², Z³, and Z⁴ is independently CR⁷, N, or NR⁹;    -   Z⁵ is C or N;    -   each of Z⁶, Z⁷, and Z⁸ is independently CR⁸, N, NR⁹, O, or S;    -   each of Z⁹, Z¹⁰, and Z¹¹ is independently CR¹⁰, CR¹¹R¹², NR¹³,        O, or S;    -   n is an integer from 0 to 6;    -   each of R², R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵,        and R¹⁶ is, at each occurrence, independently selected from H,        halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo,        carboxyl, amido, acyl, alkyl, alkenyl, alkynyl, cycloalkyl,        heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy,        alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy,        cycloalkylamino, cycloalkylalkylamino, heterocyclyl,        heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy,        heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl,        aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl,        heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy,        heteroarylamino, and heteroarylalkylamino; and    -   each of R^(A) and R^(B) is, at each occurrence, independently        selected from halo, hydroxyl, amino, cyano, dialkylphosphine        oxide, oxo, carboxyl, amido, acyl, alkyl, alkenyl, alkynyl,        cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl,        alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy,        cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino,        heterocyclyl, heterocyclylalkyl, heterocyclyloxy,        heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino,        aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino,        heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy,        heteroarylamino, and heteroarylalkylamino,    -   wherein two R^(A) groups or two R^(B) groups attached to the        same atom or different atoms can together optionally form a        bridge or ring.

In some embodiments of a compound of Formula VIII, H-VIII is selectedfrom an optionally substituted 5-membered heteroaryl. In someembodiments of a compound of Formula VIII, H-VIII is selected from anoptionally substituted 6-membered heteroaryl.

In another aspect, the present disclosure provides a compound of FormulaVIII-A:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of X¹, X², and X¹⁴ is independently CR², N, NR¹⁵, O, or S;    -   X¹¹ is CR¹⁴, N, NR¹⁵, O, or S;    -   X¹² is C or N;    -   X¹³ is a bond, CR¹⁶, or N, wherein when X¹³ is CR¹⁶ or N, then        each of X¹, X², and X¹⁴ is independently CR², N, or NR¹⁵ and X¹¹        is CR¹⁴, N, or NR¹⁵;    -   each of L¹ and L² is independently a bond, carbonyl, O, S,        —NR⁵—, —NR⁶CH₂—, —NR⁶C(═O)—, —NR⁶SO₂—, alkylene, alkenylene,        heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl, or        heteroalkylenecarbonyl;    -   A is a bond, a 3-7 membered saturated ring, or a 3-7 membered        unsaturated ring;    -   m is an integer from 0 to 12;    -   B is selected from B-I, B-II, B-III, and B-IV,    -   wherein B is connected at any ring atom to L²;    -   B-I is

-   -   B-II is

-   -   B-III is

-   -   B-IV is

-   -   each of Z¹, Z², Z³, and Z⁴ is independently CR⁷, N, or NR⁹;    -   Z⁵ is C or N;    -   each of Z⁶, Z⁷, and Z⁸ is independently CR⁸, N, NR⁹, O, or S;    -   each of Z⁹, Z¹⁰, and Z¹¹ is independently CR¹⁰, CR¹¹R¹², NR¹³,        O, or S;    -   n is an integer from 0 to 6;    -   each of R², R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵,        and R¹⁶ is, at each occurrence, independently selected from H,        halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo,        carboxyl, amido, acyl, alkyl, alkenyl, alkynyl, cycloalkyl,        heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy,        alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy,        cycloalkylamino, cycloalkylalkylamino, heterocyclyl,        heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy,        heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl,        aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl,        heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy,        heteroarylamino, and heteroarylalkylamino; and    -   each of R^(A) and R^(B) is, at each occurrence, independently        selected from halo, hydroxyl, amino, cyano, dialkylphosphine        oxide, oxo, carboxyl, amido, acyl, alkyl, alkenyl, alkynyl,        cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl,        alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy,        cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino,        heterocyclyl, heterocyclylalkyl, heterocyclyloxy,        heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino,        aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino,        heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy,        heteroarylamino, and heteroarylalkylamino,    -   wherein two R^(A) groups or two R^(B) groups attached to the        same atom or different atoms can together optionally form a        bridge or ring.

In some embodiments of a compound of Formula VIII-A, X¹ is CR²; X² isCR² or N; X¹¹ is N; X¹² is C; X¹³ is CR¹⁶; and X¹⁴ is CR². In someembodiments, X² is N. In some embodiments, X¹ and X¹³ are each CH. Insome embodiments, X¹⁴ is CR², wherein R² is aralkyl, aryloxy orarylamino, optionally wherein said aralkyl, aryloxy and arylamino aresubstituted with one or more substituents selected from halo, alkyl,—C(═O)R_(g) and —C(═O)NR_(g)R_(h), wherein R_(g) and R_(h) areindependently hydrogen or alkyl.

In some embodiments of a compound provided herein, A is cycloalkyl,heterocyclic ring, aryl or heteroaryl. In some embodiments of a compoundprovided herein, A has one of the following structures:

wherein the H of any CH or NH may be replaced with a bond to L¹, L² orR^(A). In some embodiments of a compound provided herein, A, whenpresent, is a 5-membered cycloalkyl, 6-membered cycloalkyl, 5-memberedheterocyclic ring, 6-membered heterocyclic ring, 6-membered aryl,5-membered heteroaryl, or 6-membered heteroaryl. In some embodiments, Ais a 3-6 membered saturated ring or a 3-6 membered unsaturated ring.

In some embodiments, the compound has the structure of Formula VIII-B:

In some embodiments, the compound has the structure of Formula VIII-C:

In some embodiments, the compound has the structure of Formula VIII-D:

In some embodiments, the compound has the structure of Formula VIII-E:

In some embodiments, the compound has the structure of Formula VIII-F:

In some embodiments, the compound has the structure of Formula VIII-G:

In some embodiments, the compound has the structure of Formula VIII-H:

In some embodiments of a compound provided herein, X¹¹, when present, isN.

In some embodiments of a compound provided herein, X¹³, when present, isCR¹⁶ or N. In some embodiments of a compound provided herein, X¹³, whenpresent, is a bond. In some embodiments of a compound provided herein,X¹³, when present, is a bond and X¹², when present, is N. In someembodiments of a compound provided herein, X¹³, when present, isC(CH₂)_(n).CF₃, C(CH₂)_(n).CHF₂ or C(CH₂)_(n).CH₂F, wherein n′ is 1, 2or 3.

In some embodiments of a compound provided herein, X¹⁴, when present, isC(CH₂)_(n).CF₃, C(CH₂)_(n).CHF₂ or C(CH₂)_(n).CH₂F, wherein n′ is 1, 2or 3.

In some embodiments of a compound provided herein, X¹, when present, andX¹⁴, when present, are CR².

In some embodiments of a compound provided herein, L², when present, is—CH₂—, NR⁵, —NR⁶CH₂—, —NR⁶C(═O)— or —NR⁶SO₂.

In some embodiments of a compound provided herein, m is 0. In someembodiments of a compound provided herein, m is 1, 2 or 3.

In some embodiments of a compound provided herein, R^(A), when present,is, at each occurrence, independently selected from H, halo, oxo, alkyl,haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl,aralkyl, heteroarylalkyl, heterocyclylalkyl, and cycloalkylalkyl.

In some embodiments of a compound provided herein, n is 0.

In some embodiments of a compound provided herein, n is 1 or 2.

In some embodiments of a compound provided herein, n is 1, 2 or 3.

In some embodiments of a compound provided herein, X², when present, isN.

In some embodiments of a compound provided herein, R⁵, when present, isH or alkyl.

In some embodiments of a compound provided herein, R², R¹⁴, R¹⁵ and R¹⁶,when present, are each independently H or haloalkyl. In some embodimentsof a compound provided herein, R², R¹⁴, R¹⁵ and R¹⁶, when present, areeach independently H, (CH₂)_(n).CF₃, (CH₂)_(n).CHF₂ or (CH₂)_(n).CH₂F,wherein n′ is 1, 2 or 3.

In some embodiments of a compound provided herein, each R², whenpresent, is independently H, hydroxyl, amino, alkyl, haloalkyl, amido,cycloalkyl, or aminoalkyl.

In some embodiments of a compound provided herein, each R², whenpresent, is independently H, hydroxyl, amino, alkyl, haloalkyl, amido,cycloalkyl, aminoalkyl, aralkyl, aryloxy or arylamino.

In some embodiments of a compound provided herein, each R⁷, whenpresent, is independently H, halo, hydroxy, C₁-C₄ alkyl or C₁-C₄ alkoxy.

In some embodiments of a compound provided herein, each R⁸, whenpresent, is independently H, C₁-C₄ alkyl or cyano.

In some embodiments of a compound provided herein, each R⁹, whenpresent, is independently H, C₁-C₄ alkyl, aralkyl, heteroarylalkyl,heterocyclylalkyl, or cycloalkylalkyl.

In some embodiments of a compound provided herein, each R⁹, whenpresent, is independently H, C₁-C₄ alkyl or

wherein m′ is 1, 2 or 3.

In some embodiments of a compound provided herein comprising B-II, Z¹and Z² are CR⁷; Z⁵ is C; Z⁶ is NR⁹; and Z⁷ and Z⁸ are CR⁸. In someembodiments of a compound provided herein comprising B-II, wherein: Z¹is CCH₃; Z² and Z⁸ are CH; Z⁵ is C; Z⁶ is NR⁹; and Z⁷ is CCN. In someembodiments, R⁹ is C₁-C₄ alkyl, aralkyl, heteroarylalkyl,heterocyclylalkyl, or cycloalkylalkyl, such as R⁹ is heterocyclylalkyl.

In some embodiments of a compound provided herein, at least one of R⁷,R⁸, R⁹, R¹⁰, R¹¹ or R¹³ is

wherein:

-   -   G is selected from a bond, alkylene, heteroalkylene, C₃₋₁₂        carbocycle, and 3- to 12-membered heterocycle, wherein G is        optionally substituted with one or more R³² groups;    -   V is absent or selected from a C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; wherein V is optionally substituted        with one or more R³² groups;    -   each of R²¹ and R³² is, at each occurrence, independently        selected from:        -   H, halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰,            —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰,            —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰),            —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, and —CN;        -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is            independently optionally substituted at each occurrence with            one or more substituents selected from halogen, —OR²⁰,            —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,            —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂,            —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂,            —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₃₋₁₀ carbocycle, and 3- to            10-membered heterocycle; and        -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle;        -   wherein two R³² on the same carbon atom can come together to            form a C₃₋₁₀ carbocycle or 3- to 10-membered heterocycle;        -   wherein each C₃₋₁₀ carbocycle and 3- to 10-membered            heterocycle of R³² is independently optionally substituted            with one or more substituents selected from halogen, —OR²⁰,            —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,            —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂,            —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂,            —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl,            and C₂₋₆ alkynyl;    -   R²⁰ at each occurrence is independently selected from:        -   hydrogen;        -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is            independently optionally substituted at each occurrence with            one or more substituents selected from halogen, —OR³⁰,            —SR³⁰, —N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)R³⁰, —C(O)OR³⁰,            —C(O)N(R³⁰)₂, —OC(O)R³⁰, —S(O)₂R³⁰, —S(O)₂N(R³⁰)₂,            —N(R³⁰)S(O)₂R³⁰, —NO₂, —P(O)(OR³⁰)₂, —P(O)(R³⁰)₂,            —OP(O)(OR³⁰)₂, and —CN; and        -   3- to 10-membered heterocycle and C₃₋₁₀ carbocycle; and    -   R³⁰ at each occurrence is independently selected from hydrogen,        C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of a compound provided herein, B, when present, isB-I. In some embodiments, B-I is connected to L² at a ring carbon. Insome embodiments, B-I is connected to L² at a position selected from

In some embodiments of a compound provided herein, B, when present, isB-II. In some embodiments, B-II is connected to L² at a ring carbon. Insome embodiments, B-II is connected to L² at a position selected from

In some embodiments of a compound provided herein, B, when present, isB-III. In some embodiments, B-III is connected to L² at a ring carbon.In some embodiments, B-III is connected to L² at a position selectedfrom

In some embodiments of a compound provided herein, B, when present, isB-IV. In some embodiments, B-IV is connected to L², when present, or L⁴,when present, at a ring carbon. In some embodiments, B-IV is connectedto L², when present, or L⁴, when present, at a position selected from

In some embodiments of a compound provided herein, the compound does notcomprise a functional group that covalently reacts with one or moreresidues on menin.

In some embodiments of a compound provided herein, the compound iscapable of (a) binding non-covalently to menin and (b) inhibiting theinteration of menin and MLL.

In some embodiments of a compound provided herein, one or more of R²,R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R^(A), and R^(B),when present, comprises a functional group that covalently reacts withone or more residues on menin. In some embodiments of a compoundprovided herein, the functional group covalently reacts with one or morecysteine residues on menin. In some embodiments of a compound providedherein, the functional group covalently reacts with a cysteine on meninat position 329 relative to SEQ ID NO: 2 when optimally aligned orposition 334 relative to SEQ ID NO: 1 when optimally aligned.

In some embodiments of a compound provided herein, the compound iscapable of (a) binding covalently to menin and (b) inhibiting theinteration of menin and MLL.

In some embodiments of a compound provided herein, the compoundcomprises an R², R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R^(A), or R^(B), such as R² or R^(B), selected from:

-   -   wherein:    -   G is selected from a bond, alkylene, heteroalkylene, C₃₋₁₂        carbocycle, 3- to 12-membered heterocycle, and combinations        thereof, wherein G is optionally substituted with one or more        R³² groups;    -   V is absent or selected from a C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; wherein V is optionally substituted        with one or more R³² groups;    -   each of R²¹ and R³² is, at each occurrence, independently        selected from:        -   H, halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰,            —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰,            —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰),            —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, and —CN;        -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is            independently optionally substituted at each occurrence with            one or more substituents selected from halogen, —OR²⁰,            —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,            —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂,            —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂,            —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₃₋₁₀ carbocycle, and 3- to            10-membered heterocycle; and        -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle;        -   wherein two R³² on the same carbon atom can come together to            form a C₃₋₁₀ carbocycle or 3- to 10-membered heterocycle;        -   wherein each C₃₋₁₀ carbocycle and 3- to 10-membered            heterocycle of R³² is independently optionally substituted            with one or more substituents selected from halogen, —OR²⁰,            —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,            —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂,            —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂,            —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl,            and C₂₋₆ alkynyl;    -   R²⁰ at each occurrence is independently selected from:        -   hydrogen;        -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is            independently optionally substituted at each occurrence with            one or more substituents selected from halogen, —OR³⁰,            —SR³⁰, —N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)R³⁰, —C(O)OR³⁰,            —C(O)N(R³⁰)₂, —OC(O)R³⁰, —S(O)₂R³⁰, —S(O)₂N(R³⁰)₂,            —N(R³⁰)S(O)₂R³⁰, —NO₂, —P(O)(OR³⁰)₂, —P(O)(R³⁰)₂,            —OP(O)(OR³⁰)₂, and —CN; and        -   3- to 10-membered heterocycle and C₃₋₁₀ carbocycle; and    -   R³⁰ at each occurrence is independently selected from hydrogen,        C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of a compound provided herein, R²¹ comprises afunctional group that covalently reacts with one or more residues onmenin. In some embodiments of a compound provided herein, the functionalgroup covalently reacts with one or more cysteine residues on menin. Insome embodiments of a compound provided herein, the functional groupcovalently reacts with a cysteine on menin at position 329 relative toSEQ ID NO: 2 when optimally aligned or position 334 relative to SEQ IDNO: 1 when optimally aligned.

In some embodiments of a compound provided herein, R²¹ is a moietycomprising an alpha, beta-unsaturated carbonyl; an alpha,beta-unsaturated sulfonyl; an epoxide; an aldehyde; sulfonyl fluoride; ahalomethylcarbonyl; a dihalomethylcarbonyl; or a trihalomethylcarbonyl.

In some embodiments of a compound provided herein, R²¹ is selected from:

-   -   wherein:    -   L⁵ is selected from a bond; and C₁₋₆ alkylene, C₁₋₆        heteroalkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene, each of        which is independently optionally substituted with one or more        R³² groups;    -   R²² and R²³ are selected from        -   hydrogen, halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰,            —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰,            —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰),            —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, and —CN;        -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is            independently optionally substituted at each occurrence with            one or more substituents selected from halogen, —OR²⁰,            —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,            —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂,            —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂,            —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₃₋₁₀ carbocycle, and 3- to            10-membered heterocycle; and        -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle,        -   wherein each C₃₋₁₀ carbocycle and 3- to 10-membered            heterocycle of R²² and R²³ is independently optionally            substituted with one or more substituents selected from            halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰,            —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰,            —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰),            —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₁₋₆ alkyl,            C₂₋₆ alkenyl, and C₂₋₆ alkynyl; or R²² and R²³, together            with the carbon atoms to which they are attached, form a            carbocyclic ring;    -   R²⁴ is selected from:        -   hydrogen, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰,            —S(O)₂R²⁰, and —S(O)₂N(R²⁰)₂;        -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is            independently optionally substituted at each occurrence with            one or more substituents selected from halogen, —OR²⁰,            —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,            —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂,            —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂,            —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₃₋₁₀ carbocycle, and 3- to            10-membered heterocycle; and        -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle,        -   wherein each C₃₋₁₀ carbocycle and 3- to 10-membered            heterocycle of R²⁴ is independently optionally substituted            with one or more substituents selected from halogen, —OR²⁰,            —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,            —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂,            —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂,            —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl,            and C₂₋₆ alkynyl.

In some embodiments of a compound provided herein, L⁵ is a bond. In someembodiments of a compound provided herein, L⁵ is optionally substitutedC₁₋₆ alkylene. In some embodiments of a compound provided herein, L⁵ isselected from methylene, ethylene or propylene. In some embodiments of acompound provided herein, L⁵ is substituted with one or moresubstituents selected from halogen, —NO₂, ═O, ═S, —OR²⁰, —SR²⁰, and—N(R²⁰)₂.

In some embodiments of a compound provided herein, R²³ is selected from:

-   -   hydrogen;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —OR²⁰, —SR²⁰,        —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂,        —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O,        ═S, ═N(R²⁰), —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN,        C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle; and    -   C₃₋₁₀ carbocycle, and 3- to 10-membered heterocycle,    -   wherein each C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle        is independently optionally substituted with one or more        substituents selected from halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂,        —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰,        —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S,        ═N(R²⁰), —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₁₋₆        alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of a compound provided herein, R²³ is selected from:

-   -   hydrogen;    -   C₁₋₆ alkyl optionally substituted with one or more substituents        selected from halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂, ═O, ═S, ═N(R²⁰),        and —CN; and 3- to 10-membered heterocycle optionally        substituted with one or more substituents selected from halogen,        —OR²⁰, —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,        —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂,        —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂,        —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, and        C₂₋₆ alkynyl.

In some embodiments of a compound provided herein, R²³ is selected fromhydrogen and C₁₋₆ alkyl optionally substituted with one or moresubstituents selected from halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂, ═O, ═S,═N(R²⁰), and —CN.

In some embodiments of a compound provided herein, R²² is selected from:

-   -   hydrogen and —CN;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —OR²⁰, —SR²⁰,        —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂,        —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O,        ═S, ═N(R²⁰), —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN,        C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle; and    -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle,    -   wherein each C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle        is independently optionally substituted with one or more        substituents selected from halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂,        —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰,        —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S,        ═N(R²⁰), —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₁₋₆        alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of a compound provided herein, R²² is selected fromhydrogen; —CN; and C₁₋₆ alkyl optionally substituted with one or moresubstituents selected from halogen, —OR²⁰, —SR²⁰, and —N(R²⁰)₂.

In some embodiments of a compound provided herein, R²² and R²³, togetherwith the carbon atoms to which they are attached, form a 5-, 6-, or7-membered carbocyclic ring.

In some embodiments of a compound provided herein, R²⁴ is selected fromhydrogen and C₁₋₆ alkyl optionally substituted with one or moresubstituents selected from halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂, —NO₂, ═O,and —CN.

In some embodiments of a compound provided herein, R²¹ is selected from:

In some embodiments of a compound provided herein, R²¹ is a moiety with5 to 50 atoms.

In some embodiments of a compound provided herein, R²¹ is a moiety with5 to 40 atoms.

In some embodiments, V is selected from a 3-8 membered saturated ring,3-8 membered unsaturated ring, 4-10 membered fused bicyclic ring, and5-11 membered spiro bicyclic ring. V may be optionally substituted withone or more R³² groups, such as with 1, 2, 3, 4, or 5 R³² groups. Insome embodiments, V is a 3-7 membered saturated ring, such as a 3-7membered cycloalkyl or 3-7 membered aromatic or non-aromaticheterocycle. In some embodiments, V is a 3-7 membered unsaturated ring,such as a 6 membered aryl, 5-6 membered heteroaryl, or 3-7 memberedcycloalkenyl.

In some embodiments of a compound provided herein, V is selected from a3-8 membered saturated ring optionally substituted with one or more R³²groups. In some embodiments of a compound provided herein, V is a 3-,4-, 5-, 6- or 7-membered saturated carbocycle, any one of which isoptionally substituted with one or more R³² groups. In some embodimentsof a compound provided herein, V is selected from:

any one of which is optionally substituted with one or more R³² groups.

In some embodiments of a compound provided herein, V is a 4-, 5-, 6-, 7-or 8-membered saturated heterocycle, any one of which is optionallysubstituted with one or more R³² groups. In some embodiments of acompound provided herein, V is selected from azetidine, oxetane,piperidine, oxane, piperazine, pyrrolidine, tetrahydrofuran, thiolane,imidazolidine, morpholine, thiomorpholine, azepane, and homopiperazine,any one of which is optionally substituted with one or more R³² groups.In some embodiments of a compound provided herein, V is selected from:

any one of which is optionally substituted with one or more R³² groups.

In some embodiments of a compound provided herein, V is a bicyclicheterocycle, optionally substituted with one or more R³² groups. In someembodiments of a compound provided herein, V is selected from

any one of which is optionally substituted with one or more R³² groups.

In certain embodiments, V is a 4-10 membered fused bicyclic ring, suchas a 8-10 membered fused bicyclic ring. In certain embodiments, thefused bicyclic ring includes one or more heteroatoms such as one or moreatoms selected from N, O, and S. In certain embodiments, the fusedbicyclic ring includes two heteroatoms such as two nitrogen atoms. Eachof the rings of the fused bicyclic ring may be saturated or unsaturated.In particular embodiments, both rings of the fused bicyclic ring aresaturated. Non-limiting examples of V comprising a fused bicyclic ringinclude

In some embodiments, V is a 5-11 membered spiro bicyclic ring, such as a7-11 membered spiro bicyclic ring. In certain embodiments, the fusedbicyclic ring includes one or more heteroatoms such as one or more atomsselected from N, O, and S. In particular embodiments, the fused bicyclicring includes two heteroatoms such as two nitrogen atoms. Non-limitingexamples of V comprising a spiro bicyclic ring include

In some embodiments of a compound provided herein, V is selected from anunsaturated, aromatic, or heteroaromatic ring, any one of which isoptionally substituted with one or more R³² groups. In some embodimentsof a compound provided herein, V is selected from phenyl, pyridine,pyrazine, pyrimidine, pyridazine, naphthalene, anthracene, quinoline,isoquinoline, quinoxaline, acridine, quinazoline, cinnoline,phthalazine, furan, dihydrofuran, thiophene, dihydrothiophene,imidazole, imidazoline, oxazole, oxazoline, pyrrole, dihydropyrrole,thiazole, dihydrothiazole, pyrazole, dihydropyrazole, isoxazole,dihydroisoxazole, isothiazole, dihydroisothiazole, benzofuran,isobenzofuran, indole, isoindole, benzothiophene, benzimidazole, purine,indazole, benzoxazole, benzisoxazole, and benzothiazole, any one ofwhich is optionally substituted with one or more R³² groups. In someembodiments of a compound provided herein, V is phenyl, optionallysubstituted with one or more R³² groups. In some embodiments of acompound provided herein, V is a heteroaromatic ring optionallysubstituted with one or more R³² groups. In some embodiments of acompound provided herein, V is selected from pyridine, pyrazine,pyrimidine, pyridazine, naphthalene, anthracene, quinoline,isoquinoline, quinoxaline, acridine, quinazoline, cinnoline,phthalazine, furan, thiophene, imidazole, oxazole, pyrrole, thiazole,pyrazole, isoxazole, isothiazole, benzofuran, isobenzofuran, indole,isoindole, benzothiophene, benzimidazole, purine, indazole, benzoxazole,benzisoxazole, and benzothiazole, any one of which is optionallysubstituted with one or more R³² groups. In some embodiments of acompound provided herein, V is selected from

wherein any one of which is optionally substituted with one or more R³²groups.

In some embodiments of a compound provided herein, V is absent.

In some embodiments of a compound provided herein, G is a bond.

In some embodiments of a compound provided herein, G is alkyleneoptionally substituted with one or more R³² groups.

In some embodiments of a compound provided herein, G is selected frommethylene, ethylene, propylene, and butylene, any one of which isoptionally substituted with one or more R³² groups. In some embodimentsof a compound provided herein, G is selected from:

wherein any one of which is optionally substituted with one or more R³²groups.

In some embodiments of a compound provided herein, G is a heteroalkyleneoptionally substituted with one or more R³² groups.

In some embodiments of a compound provided herein, G is a C₃₋₁₀carbocycle or 3- to 10-membered heterocycle, any one of which isoptionally substituted with one or more R³² groups.

In some embodiments of a compound provided herein, G is a saturatedC₃₋₁₀ carbocycle or saturated 3- to 10-membered heterocycle, any one ofwhich is optionally substituted with one or more R³² groups.

In some embodiments of a compound provided herein, G is selected from:

wherein any one of which is optionally substituted with one or more R³²groups.

In some embodiments, the compound is selected from Table 4h.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a compound disclosed herein and apharmaceutically acceptable carrier. In some embodiments, thepharmaceutical composition is formulated for oral administration. Insome embodiments, the pharmaceutical composition is formulated forinjection.

In yet another aspect, the present disclosure provides a method ofinhibiting the interaction of menin and one or more of MLL1, MLL2, a MLLfusion protein, and a MLL Partial Tandem Duplication, comprisingcontacting menin with an effective amount of a compound disclosedherein.

In another aspect, the present disclosure provides a method ofinhibiting the menin-MLL interaction, comprising contacting menin withan effective amount of a compound disclosed herein, wherein inhibitionof the interaction is evidenced by a reduction in the expression of aMLL fusion protein target gene, such as HOXA9, DLX2, or MEIS1.

In another aspect, the present disclosure provides a method ofstabilizing menin, comprising contacting menin with a compound disclosedherein. In some embodiments, the contacting step comprises contactingmenin with an amount of the compound sufficient to stabilize menin. Insome embodiments, the contacting step takes place in a cell.

In some embodiments of a method disclosed herein, the step of contactingcomprises contacting a cell that expresses menin. In some embodiments ofa method disclosed herein, the method comprises administering a secondtherapeutic agent to the cell. In some embodiments of a method disclosedherein, the contacting step takes place in vivo. In some embodiments ofa method disclosed herein, the contacting step takes place in vitro.

In another aspect, the present disclosure provides a method of treatinga disease or condition associated with MLL fusion proteins, comprisingadministering to a subject in need thereof an effective amount of acompound disclosed herein.

In yet another aspect, the present disclosure provides a method oftreating a disease or condition in a subject, comprising administeringto the subject a therapeutically effective amount of a pharmaceuticalcomposition of a compound disclosed herein.

In some embodiments of a method disclosed herein, the disease orcondition comprises a leukemia, hematologic malignancies, solid tumorcancer, prostate cancer, breast cancer, liver cancer, brain tumor, ordiabetes. In some embodiments, the leukemia comprises AML, ALL, MixedLineage Leukemia or leukemias with Partial Tandem Duplications of MLL.

In another aspect, the present disclosure provides a method of treatinga disorder mediated by chromosomal rearrangement on chromosome 11q23 ina subject in need thereof, the method comprising: administering to thesubject a therapeutically effective amount of a compound disclosedherein.

In yet another aspect, the present disclosure provides a method oftreating a disorder mediated by an interaction between menin and anotherprotein, comprising administering to a subject in need thereof atherapeutically effective amount of a compound disclosed herein.

In some embodiments of a method disclosed herein, the subject is ahuman.

In another aspect, the present disclosure provides a kit comprising apharmaceutical composition of a compound disclosed herein andinstructions for using the composition to treat a subject suffering froma disease or condition mediated by an interaction between menin andanother protein.

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an amino acid sequence of human menin, isoform 1 (SEQ ID NO:1).

FIG. 2 is an amino acid sequence of human menin, isoform 2 (SEQ ID NO:2).

FIG. 3 is an amino acid sequence of human menin, isoform 3 (SEQ ID NO:3).

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs.

“MLL fusion protein” refers to a protein with an N-terminal fragment ofMLL fused with a partner protein. Non-limiting examples of a partnerprotein include 11q23, 11q23.3, 11q24, 1p13.1, 1p32 (EPS15), 21q22,9p13.3, 9p22 (MLLT3/AF9), ABI1, ABI2, ACACA, ACTN4, AF1p, AFF1/AF4,AFF3/LAF4, AFF4/AF5, AKAP13, AP2A2, ARHGEF12, ARHGEF17, BCL9L, BTBD18,BUD13, C2CD3, CASC5, CASP8AP2, CBL, CBP, CEP164, CEP170B, CREBBP, DCP1A,DCPS, EEFSEC/SELB, ELL, EPS15, FLNA, FNBP1, FOXO3, GAS7, GMPS, KIAA1524,LAMC3, LOC100131626, MAML2, ME2, MLLT1/ENL, MLLT10/AF10, MLLT11/AF1Q,MLLT3/AF9, MLLT4/AF6, MLLT6/AF17, MYH11, MYO1F, NA, NEBL, NRIP3, PDS5A,PICALM, PRPF19, PTD, RUNDC3B, SEPT11, SEPT2, SEPT5, SEPT6, SEPT9, SMAP1,TET1, TNRC18, TOP3A, VAV1, and Xq26.3 (CT45A2). MLL fusion proteins maybe created through the joining of a gene that codes for an MLL proteinand a gene that codes for a partner protein creating a fusion gene.Translation of this fusion gene may result in a single or multiplepolypeptides with functional properties derived from each of theoriginal proteins.

“Amino” refers to the —NH₂ moiety.

“Carbonyl” refers to a moiety of the formula —C(═O)—.

“Carboxy” or “carboxyl” refers to the —CO₂H moiety.

“Cyano” refers to the —CN moiety.

“Hydroxy” or “hydroxyl” refers to the —OH moiety.

“Imino” refers to the ═NH moiety. Unless stated otherwise specificallyin the specification, an imino group is optionally substituted.

“Nitro” refers to the —NO₂ moiety.

“Oxo” refers to the ═O moiety.

“Thioxo” refers to the ═S moiety.

“Acyl” refers to the group —C(═O)R_(a), where R_(a) is selected from thegroup consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon), heteroalkyl, andheterocyclylalkyl. Unless stated otherwise specifically in thespecification, an acyl group is optionally substituted.

“Alkyl” refers to a straight or branched hydrocarbon chain moietyconsisting solely of carbon and hydrogen atoms, which is saturated orunsaturated (i.e., contains one or more double and/or triple bonds),having from one to twelve carbon atoms (C₁-C₁₂ alkyl), preferably one toeight carbon atoms (C₁-C₈ alkyl) or one to six carbon atoms (C₁-C₆alkyl), and which is attached to the rest of the molecule by a singlebond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl),n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl,2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl,penta-1,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Alkyl includes alkenyls (one or more carbon-carbon double bonds)and alkynyls (one or more carbon-carbon triple bonds). Unless statedotherwise specifically in the specification, an alkyl group isoptionally substituted.

“Alkoxy” refers to a moiety of the formula —OR_(a) where R_(a) is analkyl group as defined herein containing one to twelve carbon atoms.Unless stated otherwise specifically in the specification, an alkoxygroup is optionally substituted.

“Alkylamino” refers to a moiety of the formula —NHR_(a) or —NR_(a)R_(b)where R_(a) and R_(b) are each independently an alkyl group as definedherein containing one to twelve carbon atoms. Unless stated otherwisespecifically in the specification, an alkylamino group is optionallysubstituted.

“Alkylaminoalkyl” refers to an alkyl moiety comprising at least onealkylamino substituent. The alkylamino substituent can be on a tertiary,secondary or primary carbon. Unless stated otherwise specifically in thespecification, an alkylaminoalkyl group is optionally substituted.

“Amide” or “amido” refers to a moiety with formula —C(═O)NR_(a)R_(b) or—NR_(a)C(═O) R_(b), where R_(a) and R_(b) are each independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon),heteroalkyl, and heterocyclylalkyl, each of which moiety may itself beoptionally substituted. In some embodiments, it is a C₁-C₄ amido oramide group, which includes the amide carbonyl in the total number ofcarbons in the group. The R_(a)R_(b) of —NR_(a)R_(b) of the amide mayoptionally be taken together with the nitrogen to which it is attachedto form a 4-, 5-, 6-, or 7-membered ring. Unless stated otherwisespecifically in the specification, an amido group is optionallysubstituted.

“Aminoalkyl” refers to an alkyl moiety comprising at least one aminosubstituent. The amino substituent can be on a tertiary, secondary orprimary carbon. Unless stated otherwise specifically in thespecification, an aminoalkyl group is optionally substituted.

“Aminocarbonyl” refers to an amide moiety of the formula—C(═O)NR_(a)R_(b), where R_(a) and R_(b) are each independently H oralkyl. Unless stated otherwise specifically in the specification, anaminocarbonyl group is optionally substituted.

“Aryl” refers to a hydrocarbon ring system moiety comprising 6 to 18carbon atoms and at least one aromatic ring. For purposes of thisinvention, the aryl moiety is a monocyclic, bicyclic, tricyclic, ortetracyclic ring system, which may include fused or bridged ringsystems. Aryl moieties include, but are not limited to, aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane,indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, andtriphenylene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl groups that are optionally substituted.

“Aralkyl” refers to a moiety of the formula —R_(b)—R_(c) where R_(b) isan alkylene chain as defined herein and R_(c) is one or more arylmoieties as defined herein, for example, benzyl, diphenylmethyl, and thelike. Unless stated otherwise specifically in the specification, anaralkyl group is optionally substituted.

“Aralkylamino” refers to a aralkyl-NR_(a)— moiety, where R_(a) is H oralkyl. Unless stated otherwise specifically in the specification, anaralkylamino is optionally substituted.

“Aralkyloxy” refers to an aralkyl-O— moiety. Unless stated otherwisespecifically in the specification, an aralkyloxy is optionallysubstituted.

“Arylamino” refers to a —NR_(a)-aryl moiety, where R_(a) is H or alkyl.Unless stated otherwise specifically in the specification, an arylaminois optionally substituted.

“Aryloxy” refers to an —O-aryl moiety. Unless stated otherwisespecifically in the specification, an aryloxy is optionally substituted.

“Bicycloalkyl” refers to a moiety with two cycloalkyl moieties, thathave one or more atoms in common. If the cycloalkyl moieties haveexactly one atom in common they are said to be “spiro”. Examplesinclude, but are not limited to, spiro[2.2]pentane, spiro[5.5]undecane,spiro[4.5]decane, spiro[3.6]decane, and the like. If the cycloalkylmoieties have exactly two adjacent atoms in common they are said to be“fused”. Examples include, but are not limited to, bicyclo[3.1.0]hexyl,perhydronaphthyl, and the like. If the cycloalkyl moieties have morethan two atoms in common they are said to be “bridged”. Examplesinclude, but are not limited to, tricyclo[3.3.1.1]decyl (“adamantyl”),bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl (“norbornyl”),bicyclo[2.2.2]octyl, and the like. Unless stated otherwise specificallyin the specification, a bicycloalkyl is optionally substituted.

“Carboxyalkyl” refers to a moiety of the formula —R_(b)—R_(c) whereR_(b) is an alkylene chain as defined herein and R_(c) is a carboxygroup as defined herein. Unless stated otherwise specifically in thespecification, carboxyalkyl group is optionally substituted.

“Cyanoalkyl” refers to a moiety of the formula —R_(b)—R_(c) where R_(b)is an alkylene chain as defined herein and R_(c) is a cyano group asdefined herein. Unless stated otherwise specifically in thespecification, a cyanoalkyl group is optionally substituted.

“Cycloalkyl” or “carbocyclic ring” refers to a non-aromatic monocyclicor polycyclic hydrocarbon moiety, which may include fused, spiro, orbridged ring systems, having from three to fifteen carbon atoms,preferably having from three to ten carbon atoms, and which is saturatedor unsaturated and attached to the rest of the molecule by a singlebond. Monocyclic cycloalkyl moieties include, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl moieties include, forexample, adamantyl, norbornyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. A “cycloalkenyl” is acycloalkyl comprising one or more carbon-carbon double bonds within thering, such as cyclopentenyl and cyclohexenyl. Unless otherwise statedspecifically in the specification, a cycloalkyl group is optionallysubstituted.

“Carbocycle” refers to a saturated, unsaturated or aromatic ring inwhich each atom of the ring is a carbon atom. Carbocycle may include 3-to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle maybe selected from saturated, unsaturated, and aromatic rings. In someembodiments, the carbocycle is an aryl. In some embodiments, thecarbocycle is a cycloalkyl. In some embodiments, the carbocycle is acycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g.,phenyl, may be fused to a saturated or unsaturated ring, e.g.,cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated,unsaturated and aromatic bicyclic rings, as valence permits, areincluded in the definition of carbocyclic. Exemplary carbocycles includecyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, andnaphthyl. Unless stated otherwise specifically in the specification, acarbocycle is optionally substituted by one or more substituents such asthose substituents described herein.

“Cycloalkylalkyl” refers to a moiety of the formula —R_(b)R_(d) whereR_(b) is an alkylene chain as defined herein and R_(d) is a cycloalkylmoiety as defined herein. Unless stated otherwise specifically in thespecification, a cycloalkylalkyl group is optionally substituted.

“Cycloalkylalkylamino” refers to a cycloalkylalkyl-NR_(a)— moiety, whereR_(a) is H or alkyl and where the cycloalkylalkyl moiety is attached viaa carbon atom to nitrogen, wherein the nitrogen functions as a linker toattach the moiety to the remainder of the molecule. Unless statedotherwise specifically in the specification, a cycloalkylalkylamino isoptionally substituted.

“Cycloalkylalkyloxy” refers to a —O-cycloalkylalkyl moiety, where thecycloalkylalkyl moiety is attached via a carbon atom to oxygen, whereinthe oxygen functions as a linker to attach the moiety to the remainderof the molecule. Unless stated otherwise specifically in thespecification, a cycloalkylalkyloxy is optionally substituted.

“Cycloalkylamino” refers to a —NR_(a)-cycloalkyl moiety, where R_(a) isH or alkyl. Unless stated otherwise specifically in the specification, acycloalkylamino is optionally substituted.

“Cycloalkyloxy” refers to an —O-cycloalkyl moiety. Unless statedotherwise specifically in the specification, a cycloalkyloxy isoptionally substituted.

“Halo” or “halogen” refers to fluoro, chloro, bromo, or iodo.

“Haloalkyl” refers to an alkyl group, as defined herein, that issubstituted by one or more halo atoms, as defined herein, e.g.,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, —CH₂CF₃,—CH₂CHF₂, —CH₂CH₂F, —CHFCF₃, —CHFCHF₂, —CHFCH₂F, —CHFCH₃, —CF₂CF₃,—CF₂CHF₂, —CF₂CH₂F, —CF₂CH₃, —CH₂CF₂CH₃, —CH₂CHFCH₃,3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless statedotherwise specifically in the specification, a haloalkyl group isoptionally substituted.

As used herein, the term “heteroatom” or “ring heteroatom” is meant toinclude any element other than carbon or hydrogen. Preferred heteroatomsare oxygen (O), nitrogen (N), sulfur (S), and phosphorus (P).

“Heteroalkyl,” by itself or in combination with another term, means,unless otherwise stated, a straight or branched chain; monocyclic orpolycyclic moiety, which may include fused or bridged ring systems; orany combination thereof, comprising at least one carbon atom and atleast one heteroatom, such as O, N, P, Si and S, wherein one or moreheteroatoms may be oxidized. Heteroatom(s) may be positioned within thealkyl moiety, e.g., —CH₂—O—CH₂—; at a point of connectivity with theremainder of the molecule, e.g., —SO₂CH(CH₃)CH₂—; or a combinationthereof, e.g., —NH₂CH₂CH₂SO₂CH₂—. Unless stated otherwise specificallyin the specification, a heteroalkyl group is optionally substituted.

“Heteroaryl” refers to a 5- to 14-membered ring system moiety comprisingone to thirteen carbon atoms; one to six heteroatoms such as nitrogen,oxygen, and sulfur; and one or multiple rings wherein at least one ringis aromatic. For purposes of this invention, the heteroaryl group may bea monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which mayinclude fused or bridged ring systems and one or more heteroatoms may beoxidized. Examples include, but are not limited to, azepinyl, acridinyl,benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl group is optionallysubstituted.

“Heteroarylalkyl” refers to a moiety of the formula —R_(b)R_(f) whereR_(b) is an alkylene chain as defined herein and R_(f) is a heteroarylgroup as defined herein. Unless stated otherwise specifically in thespecification, a heteroarylalkyl group is optionally substituted.

“Heteroarylalkylamino” refers to a heteroarylalkyl-NR_(a)— moiety, whereR_(a) is H or alkyl. Unless stated otherwise specifically in thespecification, an heteroarylalkylamino is optionally substituted.

“Heteroarylalkyloxy” refers to an heteroarylalkyl-O— moiety. Unlessstated otherwise specifically in the specification, a heteroarylalkyloxyis optionally substituted.

“Heteroarylamino” refers to a —NR_(a)-heteroaryl moiety, where R_(a) isH or alkyl. Unless stated otherwise specifically in the specification, aheteroarylamino is optionally substituted.

“Heteroaryloxy” refers to an —O-heteroaryl moiety. Unless statedotherwise specifically in the specification, an heteroaryloxy isoptionally substituted.

“Heterobicycloalkyl” refers to a bicycloalkyl structure in which atleast one carbon ring atom is replaced with a heteroatom such as oxygen,nitrogen, and sulfur. Unless stated otherwise specifically in thespecification, a heterobicycloalkyl is optionally substituted.

“Heterocyclyl” or “heterocyclic ring” refers to a 3- to 18-memberednon-aromatic ring which consists of two to twelve carbon atoms and fromone to six heteroatoms such as nitrogen, oxygen, and sulfur. Unlessstated otherwise specifically in the specification, the heterocyclylgroup is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system,which may include fused or bridged ring systems; the heteroatoms may beoptionally oxidized; and the heterocyclyl may be unsaturated orsaturated. Examples of such heterocyclyl moieties include, but are notlimited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, a heterocyclyl group is optionally substituted.

“Heterocycle” refers to a saturated, unsaturated or aromatic ringcomprising one or more heteroatoms. Exemplary heteroatoms include N, O,Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclicrings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridgedrings. Each ring of a bicyclic heterocycle may be selected fromsaturated, unsaturated, and aromatic rings. The heterocycle may beattached to the rest of the molecule through any atom of theheterocycle, valence permitting, such as a carbon or nitrogen atom ofthe heterocycle. In some embodiments, the heterocycle is a heteroaryl.In some embodiments, the heterocycle is a heterocycloalkyl. In anexemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to asaturated or unsaturated ring, e.g., cyclohexane, cyclopentane, orcyclohexene.

“Heterocyclylalkyl” or “heterocycloalkyl” refers to a moiety of theformula —R_(b)R_(e) where R_(b) is an alkylene chain as defined hereinand R_(e) is a heterocyclyl moiety as defined herein, and if theheterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl isoptionally attached to the alkyl moiety at the nitrogen atom. Unlessstated otherwise specifically in the specification, a heterocyclylalkylgroup is optionally substituted.

“Heterocyclylalkylamino” refers to a heterocyclylalkyl-NR_(a)— moiety,where R_(a) is H or alkyl and where the heterocyclylalkyl moiety isattached via a carbon atom to nitrogen, wherein the nitrogen functionsas a linker to attach the moiety to the remainder of the molecule.Unless stated otherwise specifically in the specification, aheterocyclylalkylamino is optionally substituted.

“Heterocyclylalkyloxy” refers to a —O-heterocycloalkyl moiety, where theheterocyclylalkyl moiety is attached via a carbon atom to oxygen,wherein the oxygen functions as a linker to attach the moiety to theremainder of the molecule. Unless stated otherwise specifically in thespecification, a heterocyclylalkyloxy is optionally substituted.

“Heterocyclylamino” refers to a —NR_(a)-heterocyclyl moiety, where R_(a)is H or alkyl and where the heterocyclyl moiety is attached via a carbonatom to nitrogen, wherein the nitrogen functions as a linker to attachthe moiety to the remainder of the molecule. Unless stated otherwisespecifically in the specification, a heterocyclylamino is optionallysubstituted.

“Heterocyclyloxy” refers to an —O-heterocyclyl moiety, where theheterocyclyl moiety is attached via a carbon atom to oxygen, wherein theoxygen functions as a linker to attach the moiety to the remainder ofthe molecule. Unless stated otherwise specifically in the specification,a heterocyclyloxy is optionally substituted.

“Hydroxyalkyl” or “hydroxylalkyl” refers to an alkyl group comprising atleast one hydroxyl substituent. The —OH substituent may be on a primary,secondary, or tertiary carbon. Unless stated otherwise specifically inthe specification, a hydroxylalkyl group is optionally substituted.

“N-heteroaryl” refers to a heteroaryl moiety as defined hereincontaining at least one nitrogen and where the point of attachment ofthe heteroaryl moiety to the rest of the molecule is through a nitrogenatom in the heteroaryl ring. Unless stated otherwise specifically in thespecification, an N-heteroaryl group is optionally substituted.

“N-heterocyclyl” refers to a heterocyclyl moiety as defined hereincontaining at least one nitrogen and where the point of attachment ofthe heterocyclyl moiety to the rest of the molecule is through anitrogen atom in the heterocyclyl ring. Unless stated otherwisespecifically in the specification, a N-heterocyclyl group is optionallysubstituted.

“Thioalkyl” refers to a moiety of the formula —SR_(a) where R_(a) is analkyl moiety as defined herein containing one to twelve carbon atoms.Unless stated otherwise specifically in the specification, a thioalkylgroup is optionally substituted.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking two groups in a molecule, which may besaturated or unsaturated (i.e., contains one or more double and/ortriple bonds), and have from one to twelve carbon atoms, preferably oneto eight carbon atoms (C₁-C₈ alkylene) or one to six carbon atoms (C₁-C₆alkylene), e.g., methylene, ethylene, propylene, n-butylene, ethenylene,propenylene, n-butenylene, propynylene, n-butynylene, and the like. Thealkylene chain is attached to the rest of the molecule through a singleor double bond. The points of attachment of the alkylene chain to therest of the molecule may be through one carbon, e.g., methylene, or anytwo carbons within the chain, e.g., —CH₂CH(CH₃)CH₂CH₂—. Unless statedotherwise specifically in the specification, an alkylene chain isoptionally substituted.

“Alkylenecarbonyl” refers to a moiety of the formula —C(═O)R_(a)—, whereR_(a) is an alkylene chain as defined herein. Unless stated otherwisespecifically in the specification, an alkylenecarbonyl is optionallysubstituted.

“Alkenylene” is an unsaturated alkylene, as defined herein, whichcomprises one or more carbon-carbon double bonds. Unless statedotherwise specifically in the specification, an alkenylene is optionallysubstituted.

“Alkenylenecarbonyl” refers to an unsaturated alkylenecarbonyl, asdefined herein, which comprises one or more carbon-carbon double bonds.Unless stated otherwise specifically in the specification, analkenylenecarbonyl is optionally substituted.

“Arylene” refers to a divalent aryl group which links one part of themolecule to another part of the molecule. Unless stated specificallyotherwise, an arylene is optionally substituted.

“Heteroalkylene” refers to an alkylene group comprising at least oneheteroatom (e.g., N, O or S). In some embodiments, the heteroatom iswithin the alkylene chain (i.e., the heteroalkylene comprises at leastone carbon-heteroatom-carbon bond). In other embodiments, the heteroatomis at a terminus of the alkylene and joins the alkylene to the remainderof the molecule (e.g., M1-H-A-M2, where M1 and M2 are portions of amolecule, H is a heteroatom and A is an alkylene). A heteroalkylene mayhave both internal and terminal heteroatoms, e.g., —OCH₂CH₂OCH₂CH₂O—.Unless stated otherwise specifically in the specification, aheteroalkylene is optionally substituted.

“Heteroalkylenecarbonyl” refers to a moiety of the formula —C(═O)R_(a)—,where R_(a) is a heteroalkylene chain as defined herein. Unless statedotherwise specifically in the specification, a heteroalkylenecarbonyl isoptionally substituted.

“Heteroarylene” refers to a divalent heteroaryl group which links onepart of the molecule to another part of the molecule. Unless statedspecifically otherwise, a heteroarylene is optionally substituted.

“Heteroarylenecarbonyl” refers to a moiety of the formula —C(═O)R_(a)—,wherein R_(a) is a heteroarylene as defined herein. Unless statedspecifically otherwise, a heteroarylenecarbonyl is optionallysubstituted.

“Heterocyclylalkylene” refers to a divalent heterocyclyl group whichlinks one part of the molecule to another part of the molecule. Unlessstated specifically otherwise, a heterocycloalkylene is optionallysubstituted.

“Heterocyclylalkylenecarbonyl” refers to a moiety of the formula—C(═O)R_(a)—, wherein R_(a) is a heterocycloalkylene as defined herein.Unless stated specifically otherwise, a heterocycloalkylenecarbonyl isoptionally substituted.

The term “substituted” used herein means any of the above groups (e.g.,amino, carboxy, hydroxyl, imino, acyl, alkyl, alkenyl, alkynyl, alkoxy,alkylamino, alkylaminoalkyl, amide, aminoalkyl, aminocarbonyl, aryl,aralkyl, aralkylamino, aralkyloxy, arylamino, aryloxy, bicycloalkyl,carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkylamino, cycloalkylalkyloxy, cycloalkylamino,cycloalkyloxy, halo, haloalkyl, heteroatom, heteroalkyl, heteroaryl,heteroarylalkyl, heteroarylalkylamino, heteroarylalkyloxy,heteroarylamino, heteroaryloxy, heterobicycloalkyl, heterocyclyl,heterocyclylalkyl, heterocyclylalkylamino, heterocyclylalkyloxy,heterocyclylamino, heterocyclyloxy, hydroxyalkyl, N-heteroaryl,N-heterocyclyl, thioalkyl, alkylene, alkylenecarbonyl, alkenylene,alkenylenecarbonyl, arylene, heteroalkylene, heteroalkylenecarbonyl,heteroarylene, heteroarylenecarbonyl, heterocyclylalkylene, and/orheterocyclylalkylenecarbonyl), wherein at least one hydrogen atom isreplaced by a bond to a non-hydrogen atom such as, but not limited to: ahalogen atom such as F, Cl, Br, and I; an oxygen atom in groups such ashydroxyl groups, alkoxy groups, and ester groups; a sulfur atom ingroups such as thiol groups, thioalkyl groups, thiourea groups, sulfonegroups such as alkyl sulfone groups, sulfonyl groups such as sulfonamidegroups and sulfonylalkyl groups such as sulfonylmethane, and sulfoxidegroups such as alkyl sulfoxide groups; a nitrogen atom in groups such asamino, amines, amides, alkylamines, dialkylamines, arylamines,alkylarylamines, diarylamines, N-oxides, imides, urea, and enamines; asilicon atom in groups such as trialkylsilyl groups, dialkylarylsilylgroups, alkyldiarylsilyl groups, and triarylsilyl groups; a phosphorusatom in groups such as dialkylphosphine oxide groups, phosphine oxidegroups, phosphine groups, phosphate groups, phosphonate groups, andphosphinate groups; and other heteroatoms in various other groups.“Substituted” also means any of the above groups in which one or morehydrogen atoms are replaced by a higher-order bond (e.g., a double- ortriple-bond) to a carbon atom or a heteroatom such as oxygen in oxo,carbonyl, carboxyl, and ester groups; and nitrogen in groups such asimines, oximes, hydrazones, and nitriles. “Substituted” includes any ofthe above groups in which one or more hydrogen atoms are replaced with—NR_(g)R_(h), —NR_(g)C(═O)R_(h), —NR_(g)C(═O)NR_(g)R_(h),—NR_(g)C(═O)OR_(h), —NR_(g)SO₂R_(h), —OC(═O)NR_(g)R_(h), —OR_(g),—SR_(g), —SOR_(g), —SO₂R_(g), —OSO₂R_(g), —SO₂OR_(g), ═NSO₂R_(g),—SO₂NR_(g)R_(h), —C(═O)R_(g), —C(═O)OR_(g), —C(═O)NR_(g)R_(h),—CH₂SO₂R_(g), or —CH₂SO₂NR_(g)R_(h), where R_(g) and R_(h) areindependently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino,thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,heteroalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl,heteroaryl, N-heteroaryl and/or heteroarylalkyl. “Substituted” furthermeans any of the above groups in which one or more hydrogen atoms arereplaced by a bond to an amino, carbonyl, carboxy, cyano, hydroxyl,imino, nitro, oxo, thioxo, acyl, alkyl, alkenyl, alkynyl, alkoxy,alkylamino, alkylaminoalkyl, amide, aminoalkyl, aminocarbonyl, aryl,aralkyl, aralkylamino, aralkyloxy, arylamino, aryloxy, bicycloalkyl,carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkylamino, cycloalkylalkyloxy, cycloalkylamino,cycloalkyloxy, halo, haloalkyl, heteroatom, heteroalkyl, heteroaryl,heteroarylalkyl, heteroarylalkylamino, heteroarylalkyloxy,heteroarylamino, heteroaryloxy, heterobicycloalkyl, heterocyclyl,heterocyclylalkyl, heterocyclylalkylamino, heterocyclylalkyloxy,heterocyclylamino, heterocyclyloxy, hydroxyalkyl, N-heteroaryl,N-heterocyclyl, thioalkyl, alkylene, alkylenecarbonyl, alkenylene,alkenylenecarbonyl, arylene, heteroalkylene, heteroalkylenecarbonyl,heteroarylene, heteroarylenecarbonyl, heterocyclylalkylene,heterocyclylalkylenecarbonyl, trimethylsilanyl, dialkylphosphine oxide,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), —PO(R^(a))₂, or—PO(OR^(a))₂ group, where each R^(a) is independently hydrogen, alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl group. In addition,each of the foregoing substituents is optionally substituted with one ormore of the above substituents.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound described herein that is sufficient toaffect the intended application, including but not limited to diseasetreatment, as defined below. The therapeutically effective amount mayvary depending upon the intended treatment application (in vivo), or thesubject and disease condition being treated, e.g., the weight and age ofthe subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g., reduction ofplatelet adhesion and/or cell migration. The specific dose will varydepending on the particular compounds chosen, the dosing regimen to befollowed, whether it is administered in combination with othercompounds, timing of administration, the tissue to which it isadministered, and the physical delivery system in which it is carried.

As used herein, “treatment” or “treating” refers to an approach forobtaining beneficial or desired results with respect to a disease,disorder, or medical condition including but not limited to atherapeutic benefit and/or a prophylactic benefit. By therapeuticbenefit is meant eradication or amelioration of the underlying disorderbeing treated. Also, a therapeutic benefit is achieved with theeradication or amelioration of one or more of the physiological symptomsassociated with the underlying disorder such that an improvement isobserved in the subject, notwithstanding that the subject may still beafflicted with the underlying disorder. In certain embodiments, forprophylactic benefit, the compositions are administered to a subject atrisk of developing a particular disease, or to a subject reporting oneor more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompass administrationof two or more agents to an animal, including humans, so that bothagents and/or their metabolites are present in the subject at the sametime. Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

“Pharmaceutically acceptable salt” includes both pharmaceuticallyacceptable acid addition salts and pharmaceutically acceptable baseaddition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise desirable, and which areformed with inorganic acids such as, but are not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, or organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise desirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

The terms “antagonist” and “inhibitor” are used interchangeably, andthey refer to a compound having the ability to inhibit a biologicalfunction (e.g., activity, expression, binding, protein-proteininteraction) of a target protein (e.g., menin, MLL1, MLL2, and/or a MLLfusion protein). Accordingly, the terms “antagonist” and “inhibitor” aredefined in the context of the biological role of the target protein.While preferred antagonists herein specifically interact with (e.g.,bind to) the target, compounds that inhibit a biological activity of thetarget protein by interacting with other members of the signaltransduction pathway of which the target protein is a member are alsospecifically included within this definition. A preferred biologicalactivity inhibited by an antagonist is associated with the development,growth, or spread of a tumor.

The term “agonist” as used herein refers to a compound having theability to initiate or enhance a biological function of a targetprotein, whether by inhibiting the activity or expression of the targetprotein. Accordingly, the term “agonist” is defined in the context ofthe biological role of the target polypeptide. While preferred agonistsherein specifically interact with (e.g., bind to) the target, compoundsthat initiate or enhance a biological activity of the target polypeptideby interacting with other members of the signal transduction pathway ofwhich the target polypeptide is a member are also specifically includedwithin this definition.

As used herein, “agent” or “biologically active agent” refers to abiological, pharmaceutical, or chemical compound. Non-limiting examplesinclude a simple or complex organic or inorganic molecule, a peptide, aprotein, an oligonucleotide, an antibody, an antibody derivative,antibody fragment, a vitamin derivative, a carbohydrate, a toxin, and achemotherapeutic compound. Various compounds can be synthesized, forexample, small molecules and oligomers (e.g., oligopeptides andoligonucleotides), and synthetic organic compounds based on various corestructures. In addition, various natural sources can provide compoundsfor screening, such as plant or animal extracts, and the like.

“Signal transduction” is a process during which stimulatory orinhibitory signals are transmitted into and within a cell to elicit anintracellular response. A modulator of a signal transduction pathwayrefers to a compound which modulates the activity of one or morecellular proteins mapped to the same specific signal transductionpathway. A modulator may augment (agonist) or suppress (antagonist) theactivity of a signaling molecule.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.One class of anti-cancer agents comprises chemotherapeutic agents.“Chemotherapy” means the administration of one or more chemotherapeuticdrugs and/or other agents to a cancer patient by various methods,including intravenous, oral, intramuscular, intraperitoneal,intravesical, subcutaneous, transdermal, buccal, or inhalation or in theform of a suppository.

The term “cell proliferation” refers to a phenomenon by which the cellnumber has changed as a result of division. This term also encompassescell growth by which the cell morphology has changed (e.g., increased insize) consistent with a proliferative signal.

“Subject” refers to an animal, such as a mammal, for example a human.The methods described herein can be useful in both human therapeuticsand veterinary applications. In some embodiments, the subject is amammal, and in some embodiments, the subject is human.

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets (e.g., cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildlife andthe like.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein (e.g., compound of Formula VIII). Thus, theterm “prodrug” refers to a precursor of a biologically active compoundthat is pharmaceutically acceptable. In some aspects, a prodrug isinactive when administered to a subject but is converted in vivo to anactive compound, for example, by hydrolysis. The prodrug compound oftenoffers advantages of solubility, tissue compatibility or delayed releasein a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs(1985), pp. 7-9, 21-24 (Elsevier, Amsterdam); Higuchi, T., et al.,“Pro-drugs as Novel Delivery Systems,” (1987) A.C.S. Symposium Series,Vol. 14; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche,American Pharmaceutical Association and Pergamon Press) each of which isincorporated in full by reference herein. The term “prodrug” is alsomeant to include any covalently bonded carriers, which release theactive compound in vivo when such prodrug is administered to a mammaliansubject. Prodrugs of an active compound, as described herein, aretypically prepared by modifying functional groups present in the activecompound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent active compound. Prodrugsinclude compounds wherein a hydroxy, amino or mercapto group is bondedto any group that, when the prodrug of the active compound isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of a hydroxy functional group, or acetamide, formamide andbenzamide derivatives of an amine functional group in the activecompound and the like.

The term “in vivo” refers to an event that takes place in a subject'sbody.

The term “in vitro” refers to an event that takes places outside of asubject's body. For example, an in vitro assay encompasses any assay runoutside of a subject. In vitro assays encompass cell-based assays inwhich cells alive or dead are employed. In vitro assays also encompass acell-free assay in which no intact cells are employed.

In certain embodiments, the compounds disclosed herein are isotopicallylabeled. Isotopically-labeled compounds (e.g., an isotopologue) may haveone or more atoms replaced by an atom having a different atomic mass ormass number. Non-limiting examples of isotopes that can be incorporatedinto the disclosed compounds include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Certain isotopically-labeledcompounds, for example, those incorporating a radioactive isotope, areuseful in drug and/or substrate tissue distribution studies. Theradioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, areparticularly useful for this purpose in view of their ease ofincorporation and ready means of detection. These radiolabeled compoundscould be useful to help determine or measure the effectiveness of thecompounds, by characterizing, for example, the site or mode of action,or binding affinity to a pharmacologically important site of action.Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence are preferred in some circumstances.Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundscan generally be prepared by conventional techniques known to thoseskilled in the art or by processes analogous to those described in thePreparations and Examples as set out below using an appropriateisotopically-labeled reagent in place of the non-labeled reagent.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl group may or may not be substituted and that the descriptionincludes both substituted aryl groups and aryl groups having nosubstitution.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye, colorant, flavor enhancer,surfactant, wetting agent, dispersing agent, suspending agent,stabilizer, isotonic agent, solvent, or emulsifier which has beenapproved by the United States Food and Drug Administration as beingacceptable for use in humans or domestic animals.

The compounds of the invention, or their pharmaceutically acceptablesalts may contain one or more asymmetric centers and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that aredefined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. A “stereoisomer” refers to a compound made up of the same atomsbonded by the same bonds but having different three-dimensionalstructures, which are not interchangeable. The present inventioncontemplates various stereoisomers and mixtures thereof and includes“enantiomers”, which refers to two stereoisomers whose molecules arenonsuperimposeable mirror images of one another. Optically active (+)and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared usingchiral synthons or chiral reagents, or resolved using conventionaltechniques, for example, chromatography and fractional crystallization.Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC). When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any the compounds and all tautomeric forms are alsointended to be included.

Compounds

The present disclosure provides compounds for modulating the interactionof menin with proteins such as MLL1, MLL2 and MLL-fusion oncoproteins.In certain embodiments, the disclosure provides compounds and methodsfor inhibiting the interaction of menin with its upstream or downstreamsignaling molecules including but not limited to MLL1, MLL2 andMLL-fusion oncoproteins. Compounds of the disclosure may be used inmethods for the treatment of a wide variety of cancers and otherdiseases associated with one or more of MLL1, MLL2, MLL fusion proteins,and menin. In certain embodiments, a compound of the disclosurecovalently binds menin and inhibits the interaction of menin with MLL.In certain embodiments, a compound of the disclosure interactsnon-covalently with menin and inhibits the interaction of menin withMLL.

Compounds of the disclosure may be used in methods for treating a widevariety of diseases associated with MLL1, MLL2, MLL fusion proteins, andmenin. In certain embodiments, a compound of the disclosure interactsnon-covalently with menin and inhibits the interaction of menin withMLL. In certain embodiments, a compound of the disclosure covalentlybinds menin and inhibits the interaction of menin with MLL.

In an aspect, the invention provides compounds which are capable ofselectively binding to the menin protein and/or modulating menin'sinteraction with an MLL protein (e.g., MLL1, MLL2, MLL fusion protein).In some embodiments, the compounds modulate the menin protein by bindingto or interacting with one or more amino acids and/or one or more metalions. Some compounds may occupy the F9 and/or P13 pocket on menin. Thebinding of these compounds may disrupt menin or MLL (non-limitingexamples include MLL1, MLL2, and MLL fusion proteins) downstreamsignaling.

In some embodiments, provided herein is a compound having the structureof Formula VIII:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   H-VIII is selected from an optionally substituted 5-membered        heteroaryl, an optionally substituted 6-membered aryl, and an        optionally substituted 6-membered heteroaryl,    -   wherein ring carbons of H-VIII are, at each occurrence,        independently optionally substituted with R², R¹⁴, or R¹⁶ and        ring nitrogens of H-VIII are, at each occurrence, independently        optionally substituted with R¹⁵;    -   each of L¹ and L² is independently a bond, carbonyl, O, S,        —NR⁵—, —NR⁶CH₂—, —NR⁶C(═O)—, —NR⁶SO₂—, alkylene, alkenylene,        heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl, or        heteroalkylenecarbonyl;    -   A is a bond, a 3-7 membered saturated ring, or a 3-7 membered        unsaturated ring;    -   m is an integer from 0 to 12;    -   B is selected from B-I, B-II, B-III, and B-IV,    -   wherein B is connected at any ring atom to L²;    -   B-I is

-   -   B-II is

-   -   B-III is

-   -   B-IV is

-   -   each of Z¹, Z², Z³, and Z⁴ is independently CR⁷, N, or NR⁹;    -   Z⁵ is C or N;    -   each of Z⁶, Z⁷, and Z⁸ is independently CR⁸, N, NR⁹, O, or S;    -   each of Z⁹, Z¹⁰, and Z¹¹ is independently CR¹⁰, CR¹¹R¹², NR¹³,        O, or S;    -   n is an integer from 0 to 6;    -   each of R², R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵,        and R¹⁶ is, at each occurrence, independently selected from H,        halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo,        carboxyl, amido, acyl, alkyl, alkenyl, alkynyl, cycloalkyl,        heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy,        alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy,        cycloalkylamino, cycloalkylalkylamino, heterocyclyl,        heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy,        heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl,        aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl,        heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy,        heteroarylamino, and heteroarylalkylamino; and    -   each of R^(A) and R^(B) is, at each occurrence, independently        selected from halo, hydroxyl, amino, cyano, dialkylphosphine        oxide, oxo, carboxyl, amido, acyl, alkyl, alkenyl, alkynyl,        cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl,        alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy,        cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino,        heterocyclyl, heterocyclylalkyl, heterocyclyloxy,        heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino,        aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino,        heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy,        heteroarylamino, and heteroarylalkylamino,    -   wherein two R^(A) groups or two R^(B) groups attached to the        same atom or different atoms can together optionally form a        bridge or ring.

In various different embodiments, the compound has one of the structuresset forth in one of the following tables. In various differentembodiments, the compound comprises one or more of the structures setforth in one or more of the following tables.

Ring H-VIII

In some cases, for a compound of Formula VIII, H-VIII is selected froman optionally substituted 5-membered heteroaryl, an optionallysubstituted 6-membered aryl, and an optionally substituted 6-memberedheteroaryl. In some cases, ring carbons of H-VIII are, at eachoccurrence, independently optionally substituted with R², R¹⁴, or R¹⁶.In some cases, ring nitrogens of H-VIII are, at each occurrence,independently optionally substituted with R¹⁵. In some cases, H-VIII isselected from an optionally substituted 5-membered heteroaryl and anoptionally substituted 6-membered heteroaryl.

In some cases, for a compound of Formula VIII, H-VIII has the structureof H-VIII-1:

In some cases, each of X¹, X², and X¹⁴ is independently selected fromCR², N, NR¹⁵, O, and S. In some cases, X¹¹ is selected from CR¹⁴, N,NR¹⁵, O, and S. In some cases, X¹² is C or N. In some cases, X¹³ is abond, CR¹⁶, or N. In some cases, when X¹³ is CR¹⁶ or N, then each of X¹,X², and X¹⁴ is independently CR², N, or NR¹⁵ and X¹¹ is CR¹⁴, N, orNR¹⁵. In some cases, when X¹³ is CR¹⁶, then X¹¹ is N. In some cases,when X¹³ is CR¹⁶, then X¹² is C. In some cases, X¹ is CR²; X² is CR orN; X¹¹ is N; X¹² is C; X¹³ is CR¹⁶; and X¹⁴ is CR². In some cases, X¹⁴is N, optionally wherein X¹ and X¹³ are each CH. In some cases, X² isCR², wherein R² is aralkyl, aryloxy or arylamino. Said aralkyl, aryloxyand arylamino may be substituted with one or more substitutents selectedfrom halo, alkyl, —C(═O)R_(g) and —C(═O)NR_(g)R_(h), wherein R_(g) andR_(h) are independently hydrogen or alkyl. In some cases, H-VIII has thestructure of H-VIII-10. In some cases, H-VIII does not contain three ormore adjacent ring N atoms. In some cases, H-VIII is selected from astructure listed in Table 1e. In some cases, H-VIII is not one or morestructures listed in Table 1e.

In a compound of Formula VIII, H-VIII may contain one or moreheteroatoms. In some cases, H-VIII contains 0, 1, 2, 3, or 4 ringheteroatoms. In some cases, H-VIII contains at least 1, 2, 3, or 4 ringheteroatoms. In some cases, H-VIII contains up to 1, 2, 3, or 4 ringheteroatoms. In some cases, H-VIII contains 0, 1, 2, 3, or 4 ring Natoms. In some cases, H-VIII contains at least 1, 2, 3, or 4 ring Natoms. In some cases, H-VIII contains up to 1, 2, 3, or 4 ring N atoms.In some cases, H-VIII contains 0 or 1 ring O atoms. In some cases,H-VIII contains at least 1 ring O atom. In some cases, H-VIII containsup to 1 ring O atom. In some cases, H-VIII contains 0 or 1 ring S atoms.In some cases, H-VIII contains at least 1 ring S atom. In some cases,H-VIII contains up to 1 ring S atom. In some cases, H-VIII contains 2,3, 4, 5, or 6 ring carbon atoms. In some cases, H-VIII contains at least2, 3, 4, 5, or 6 ring carbon atoms. In some cases, H-VIII contains up to2, 3, 4, 5, or 6 ring carbon atoms.

TABLE 1e Non-limiting examples of H-VIII structures H-VIII Number H-VIIIStructure H-VIII-1

H-VIII-2

H-VIII-3

H-VIII-4

H-VIII-5

H-VIII-6

H-VIII-7

H-VIII-8

H-VIII-9

H-VIII-10

H-VIII-11

H-VIII-12

H-VIII-13

H-VIII-14

H-VIII-15

H-VIII-16

H-VIII-17

H-VIII-18

H-VIII-19

H-VIII-20

H-VIII-21

Ring A

In a compound of Formula VIII, A may be a bond, a 3-7 membered saturatedring, or a 3-7 membered unsaturated ring. In some cases, A is aromatic,non-aromatic, saturated, or unsaturated. In some cases, A is an aryl,arylene, cycloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkylene,heteroaryl, heteroarylene, or N-heteroaryl. In some cases, A is a 3, 4,5, 6, or 7-membered ring. In some cases, A is at least a 3, 4, 5, 6, or7-membered ring. In some cases, A is up to a 3, 4, 5, 6, or 7-memberedring. In some cases, A is a bond. In some cases, A is a 3-6 memberedsaturated ring or a 3-6 membered unsaturated ring. In some cases, A is a3-6 membered saturated ring.

In a compound of Formula VIII, A may contain one or more heteroatoms. Insome cases, A contains 0, 1, 2, 3, or 4 ring heteroatoms. In some cases,A contains at least 1, 2, 3, or 4 ring heteroatoms. In some cases, Acontains up to 1, 2, 3, or 4 ring heteroatoms. In some cases, A contains0, 1, 2, 3, or 4 ring N atoms. In some cases, A contains at least 1, 2,3, or 4 ring N atoms. In some cases, A contains up to 1, 2, 3, or 4 ringN atoms. In some cases, A contains 0, 1, 2, or 3 ring O atoms. In somecases, A contains at least 1, 2, or 3 ring O atoms. In some cases, Acontains up to 1, 2, or 3 ring O atoms. In some cases, A contains 0, 1,or 2 ring S atoms. In some cases, A contains at least 1 or 2 ring Satoms. In some cases, A contains up to 1 or 2 ring S atoms. In somecases, A contains 2, 3, 4, 5, 6, or 7 ring carbon atoms. In some cases,A contains at least 2, 3, 4, 5, 6, or 7 ring carbon atoms. In somecases, A contains up to 2, 3, 4, 5, 6, or 7 ring carbon atoms.

In a compound of Formula VIII, A may be connected at any ring atom to L¹or L² (e.g., by replacing a hydrogen connected to a ring atom with abond to L¹ or L²). In some cases, A is connected at the same ring atomto L¹ and L². In some cases, A is connected at different ring atoms toL¹ and L². In some cases, A is connected at a ring heteroatom to L¹and/or L². In some cases, the ring heteroatom is a N. In some cases, Ais connected at a ring carbon to L¹ and/or L². In some cases, A isconnected at a ring heteroatom to one of L¹ and L² and at a ring carbonto the other of L¹ or L². In some cases, A is connected at the ring atomin position 1, 2, 3, 4, 5, 6, or 7 to L¹. In some cases, A is connectedat the ring atom in position 1, 2, 3, 4, 5, 6, or 7 to L².

In a compound of Formula VIII, A may be optionally substituted with oneor more R^(A) groups (e.g., by replacing a hydrogen connected to a ringatom with a bond to R^(A)). A may be optionally substituted with 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 R^(A) groups. A may be optionallysubstituted with at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 R^(A)groups. A may be optionally substituted with up to 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, or 12 R^(A) groups. In some cases, A is not substituted.In some cases, A is optionally substituted with m R^(A) groups. In somecases, m is an integer from 0 to 12. In some cases, m is 0, 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, or 12. In some cases, m at least 0, 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, or 12. In some cases, m is up to 0, 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, or 12. In some cases, A is optionally substitutedwith p R^(A) groups. In some cases, p is an integer from 1 to 9. In somecases, p is 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some cases, p is at least1, 2, 3, 4, 5, 6, 7, 8, or 9. In some cases, p is up to 1, 2, 3, 4, 5,6, 7, 8, or 9. In some cases, R^(A) is, at each occurrence,independently selected from halo, hydroxyl, amino, cyano,dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, alkenyl,alkynyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl,alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy,cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl,heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino,heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino,aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy,heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino. An R^(A)group may be connected to any ring atom of A. In some cases, an R^(A)group is connected to a ring carbon of A. In some cases, an R^(A) groupis connected to a ring heteroatom of A. In some cases, an R^(A) group isconnected to the ring atom in position 1, 2, 3, 4, 5, 6, or 7 of A. Insome cases, two R^(A) groups may be connected to the same ring atom ofA. In some cases, only one R^(A) group may be connected to each ringatom of A. In some cases, two R^(A) groups attached to the same atom ordifferent atoms can together optionally form a bridge or ring. In somecases, two R^(A) groups attached to the same atom or different atoms cantogether optionally be an alkylene, alkylenecarbonyl, alkenylene,alkenylenecarbonyl, arylene, heteroalkylene, heteroalkylenecarbonyl,heteroarylene, heteroarylenecarbonyl, heterocyclylalkylene, orheterocyclylalkylenecarbonyl.

In some cases, for a compound of Formula VIII, A is selected from a ringA structure listed in Table 2. In some cases, A is selected from A-1 toA-101 and any combination thereof. In some cases, A is selected from A-1to A-18, A-40 to A-42, A-44, A-50 to A-57, A-78 to A-87, A-90, A-92,A-95 to A-101, and any combination thereof. In some cases, A is not oneor more ring A structures listed in Table 2. In some cases, A is not 1,2, 3, 4, 5, 6, or 7 ring A structures selected from the group consistingof ring A structures A-7, A-8, A-9, A-10, A-16, A-17, and A-18. In somecases, a ring A structure in Table 2 may contain one or more R^(A)groups and may be optionally substituted with one or more additionalR^(A) groups.

TABLE 2 Non-limiting examples of Ring A structures Ring A Number Ring AStructure A-1

A-2

A-3

A-4

A-5

A-6

A-7

A-8

A-9

A-10

A-11

A-12

A-13

A-14

A-15

A-16

A-17

A-18

A-19

A-20

A-21

A-22

A-23

A-24

A-25

A-26

A-27

A-28

A-29

A-30

A-31

A-32

A-33

A-34

A-35

A-36

A-37

A-38

A-39

A-40

A-41

A-42

A-43

A-44

A-45

A-46

A-47

A-48

A-49

A-50

A-51

A-52

A-53

A-54

A-55

A-56

A-57

A-58

A-59

A-60

A-61

A-62

A-63

A-64

A-65

A-66

A-67

A-68

A-69

A-70

A-71

A-72

A-73

A-74

A-75

A-76

A-77

A-78

A-79

A-80

A-81

A-82

A-83

A-84

A-85

A-86

A-87

A-88

A-89

A-90

A-91

A-92

A-93

A-94

A-95

A-96

A-97

A-98

A-99

A-100

A-101

L¹ and L²

In some cases, for a compound of Formula VIII, each of L¹ and L² isindependently a bond, carbonyl, O, S, —NR⁵—, —NR⁶CH₂—, —NR⁶C(═O)—,—NR⁶SO₂—, alkylene, alkenylene, heteroalkylene, alkylenecarbonyl,alkenylenecarbonyl, or heteroalkylenecarbonyl. In some cases, analkylene is a C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, or C₁₂alkylene. In some cases, an alkylene is up to a C₁, C₂, C₃, C₄, C₅, C₆,C₇, C₈, C₉, C₁₀, C₁₁, or C₁₂ alkylene. In some cases, an alkylene is atleast a C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, or C₁₂ alkylene.In some cases, an alkylene contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,or 12 chain carbons. In some cases, an alkylene contains up to 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, or 12 chain carbons. In some cases, analkylene contains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12chain carbons. In some cases, an alkylene contains 0, 1, 2, 3, 4, 5, 6,or 7 double and/or triple bonds. In some cases, an alkylene contains upto 1, 2, 3, 4, 5, 6, or 7 double and/or triple bonds. In some cases, analkylene contains at least 1, 2, 3, 4, 5, 6, or 7 double and/or triplebonds. In some cases, an alkylene chain is attached to the rest of themolecule through a single or double bond and to the radical groupthrough a single or double bond. In some cases, an alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. In some cases, the points ofattachment of the alkylene chain to the rest of the molecule and to theradical group are through one carbon or any two carbons within thechain. In some cases, the points of attachment of the alkylene chain tothe rest of the molecule and to the radical group can be through onecarbon within the chain. In some cases, the points of attachment of thealkylene chain to the rest of the molecule and to the radical group canbe through any two carbons within the chain. In some cases, analkenylene contains 1, 2, 3, 4, 5, 6, or 7 double bonds. In some cases,an alkenylene contains up to 1, 2, 3, 4, 5, 6, or 7 double bonds. Insome cases, an alkenylene contains at least 1, 2, 3, 4, 5, 6, or 7double bonds. In some cases, a heteroalkylene contains 1, 2, 3, 4, 5, 6,7, 8, 9, or 10 chain heteroatoms. In some cases, a heteroalkylenecontains up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 chain heteroatoms. Insome cases, a heteroalkylene contains at least 1, 2, 3, 4, 5, 6, 7, 8,9, or 10 chain heteroatoms. In some cases, the heteroatom or heteroatomsare within the alkylene chain. In some cases, the heteroatom orheteroatoms are one or two termini of the alkylene and join the alkyleneto the remainder of the molecule and/or to the radical group.

In some cases, for a compound of Formula VIII, L¹ and L², when present,are each independently selected from bond, —O—, —S—, —N(R⁵¹)—,—N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹), —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂₋,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂O—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹),—N(R⁵¹)S(O)N(R⁵¹)—; alkylene, alkenylene, alkynylene, heteroalkylene,heteroalkenylene, and heteroalkynylene, each of which is optionallysubstituted with one or more R⁵⁰, wherein two R⁵⁰ groups attached to thesame atom or different atoms of any one of L¹ and L² can togetheroptionally form a bridge or ring;

-   -   R⁵⁰ is independently selected at each occurrence from:        -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,            —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,            —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,            —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,            —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,            —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂,            —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²);        -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which            is independently optionally substituted at each occurrence            with one or more substituents selected from halogen, —NO₂,            —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,            —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,            —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,            —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,            —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,            —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂,            —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂ carbocycle, and 3- to            12-membered heterocycle; and        -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,        -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered            heterocycle in R⁵⁰ is independently optionally substituted            with one or more substituents selected from halogen, —NO₂,            —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,            —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,            —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,            —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,            —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,            —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂,            —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl,            C₂₋₆ alkenyl, and C₂₋₆ alkynyl;    -   R⁵¹ is independently selected at each occurrence from:        -   hydrogen, —C(O)R⁵², —C(O)OR⁵², and —C(O)N(R⁵²)₂,            —C(O)NR⁵³R⁵⁴;        -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is            independently optionally substituted at each occurrence with            one or more substituents selected from halogen, —NO₂, —CN,            —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,            —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,            —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,            —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,            —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,            —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂,            —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂ carbocycle and 3- to            12-membered heterocycle; and        -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,        -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered            heterocycle in R⁵¹ is independently optionally substituted            with one or more substituents selected from halogen, —NO₂,            —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,            —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,            —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,            —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,            —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,            —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂,            —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl,            C₂₋₆ alkenyl, and C₂₋₆ alkynyl;    -   R⁵² is independently selected at each occurrence from hydrogen;        and C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered        heteroalkyl, C₃₋₁₂ carbocycle, and 3- to 12-membered        heterocycle, each of which is optionally substituted by halogen,        —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,        C₃₋₁₂ carbocycle, and 3- to 6-membered heterocycle; and    -   R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which        they are attached to form a heterocycle, optionally substituted        with one or more R⁵⁰.

Ring B

In some cases, for a compound of Formula VIII, B is monocyclic orbicyclic (e.g., two fused rings). In some cases, B is a bicyclic ringsystem comprising a 6-membered ring. In some cases, B is a bicyclic ringsystem comprising a 6-membered ring fused to a 5-membered ring. In somecases, B is a bicyclic ring system comprising a 6-membered ring fused toa 6-membered ring. In some cases, one or two rings of B are aromatic,non-aromatic, saturated, or unsaturated. In some cases, one or two ringsof B are an aryl, arylene, cycloalkyl, heterocyclyl, N-heterocyclyl,heteroaryl, heteroarylene, or N-heteroaryl. In some cases, B is selectedfrom B-I, B-II, B-III, B-IV, and any combination thereof, where B-I is

B-III is

and B-IV is

In some cases, each of Z¹, Z², Z³, and Z⁴ is independently CR⁷, N, orNR⁹. In some cases, Z⁵ is C or N. In some cases, each of Z⁶, Z⁷, and Z⁸is independently CR⁸, N, NR⁹, O, or S. In some cases, each of Z⁹, Z¹⁰,and Z¹¹ is independently CR¹⁰, CR¹¹R¹², NR¹³, O, or S.

B or any one of B-I, B-II, B-III, or B-IV may contain one or moreheteroatoms. In some cases, B or any one of B-I, B-II, B-III, or B-IVcontains 0, 1, 2, 3, 4, or 5 ring heteroatoms. In some cases, B or anyone of B-I, B-II, B-III, or B-IV contains at least 1, 2, 3, 4, or 5 ringheteroatoms. In some cases, B or any one of B-I, B-II, B-III, or B-IVcontains up to 1, 2, 3, 4, or 5 ring heteroatoms. In some cases, B orany one of B-I, B-II, B-III, or B-IV contains 0, 1, 2, 3, or 4 ring Natoms. In some cases, B or any one of B-I, B-II, B-III, or B-IV containsat least 1, 2, 3, or 4 ring N atoms. In some cases, B or any one of B-I,B-II, B-III, or B-IV contains up to 1, 2, 3, or 4 ring N atoms. In somecases, B or any one of B-I, B-II, B-III, or B-IV contains 0, 1, or 2ring O atoms. In some cases, B or any one of B-I, B-II, B-III, or B-IVcontains at least 1 or 2 ring O atoms. In some cases, B or any one ofB-I, B-II, B-III, or B-IV contains up to 1 or 2 ring O atoms. In somecases, B or any one of B-I, B-II, B-III, or B-IV contains 0, 1, or 2ring S atoms. In some cases, B or any one of B-I, B-II, B-III, or B-IVcontains at least 1 or 2 ring S atoms. In some cases, B or any one ofB-I, B-II, B-III, or B-IV contains up to 1 or 2 ring S atoms. In somecases, B or any one of B-I, B-II, B-III, or B-IV contains 3, 4, 5, 6, 7,8, 9, or 10 ring carbon atoms. In some cases, B or any one of B-I, B-II,B-III, or B-IV contains at least 3, 4, 5, 6, 7, 8, 9, or 10 ring carbonatoms. In some cases, B or any one of B-I, B-II, B-III, or B-IV containsup to 3, 4, 5, 6, 7, 8, 9, or 10 ring carbon atoms.

In a compound of Formula VIII, B or any one of B-I, B-II, B-III, or B-IVmay be connected at any ring atom to L² (e.g., by replacing a hydrogenconnected to a ring atom with a bond to L²). In some cases, B or any oneof B-I, B-II, B-III, or B-IV is connected at a ring heteroatom to L². Insome cases, the ring heteroatom is a N. In some cases, B or any one ofB-I, B-II, B-III, or B-IV is connected at a ring carbon to L². In somecases, B or any one of B-I, B-II, B-III, or B-IV is connected at a ringatom of an aromatic ring to L². In some cases, B or any one of B-I,B-II, B-III, or B-IV is connected at a ring atom of a non-aromatic ringto L². In some cases, B or any one of B-I, B-II, B-III, or B-IV isconnected at a ring atom of a 6-membered ring to L². In some cases, B orany one of B-I, B-II, B-III, or B-IV is connected at a ring atom of a5-membered ring to L². In some cases, B or any one of B-I, B-II, B-III,or B-IV is connected at a ring atom of a benzene ring. In some cases, Bor any one of B-I, B-II, B-III, or B-IV is connected at a ring atom of anon-benzene ring. In some cases, B or any one of B-I, B-II, B-III, orB-IV is connected at the ring atom in position 1, 2, 3, 4, 5, 6, 7, or 8to L².

In some cases, for a compound of Formula VIII, B-I or any one of B-I-2to B-I-20 is connected to L² at a position selected from

and any combination thereof. In some cases, B-I or any one of B-I-2 toB-I-24 is connected to L² at a position selected from

and any combination thereof. In some cases, B-II or any one of B-II-2 toB-II-52 is connected to L² at a position selected from

and any combination thereof. In some cases, B-III or any one of B-III-2to B-III-12 is connected to L² at a position selected from

and any combination thereof. In some cases, B-III or any one of B-III-2to B-III-13 is connected to L² at a position selected from

and any combination thereof. In some cases, B-IV or any one of B-IV-2 toB-IV-27 is connected to L² at a position selected from

and any combination thereof.

In a compound of Formula VIII, B may be optionally substituted with oneor more R^(B) groups (e.g., by replacing a hydrogen connected to a ringatom with a bond to R^(B)). B may be optionally substituted with 0, 1,2, 3, 4, 5, or 6 R^(B) groups. B may be optionally substituted with atleast 1, 2, 3, 4, 5, or 6 R^(B) groups. B may be optionally substitutedwith up to 1, 2, 3, 4, 5, or 6 R^(B) groups. In some cases, B is notsubstituted. In some cases, B is optionally substituted with n R^(B)groups. In some cases, n is an integer from 0 to 6. In some cases, n is0, 1, 2, 3, 4, 5, or 6. In some cases, n is at least 0, 1, 2, 3, 4, 5,or 6. In some cases, n is up to 0, 1, 2, 3, 4, 5, or 6. In some cases,R^(B) is, at each occurrence, independently selected from halo,hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido,acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, haloalkyl,aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl,cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino,cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy,heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl,aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl,heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, andheteroarylalkylamino. An R^(B) group may be connected to any ring atomof B. In some cases, an R^(B) group is connected to a ring carbon of B.In some cases, an R^(B) group is connected to a ring heteroatom of B. Insome cases, an R^(B) group is connected to the ring atom in position 1,2, 3, 4, 5, 6, 7, or 8 of B. In some cases, two R^(B) groups may beconnected to the same ring atom of B. In some cases, only one R^(B)group may be connected to each ring atom of B. In some cases, two R^(B)groups attached to the same atom or different atoms can togetheroptionally form a bridge or ring. In some cases, two R^(B) groupsattached to the same atom or different atoms can together optionally bean alkylene, alkylenecarbonyl, alkenylene, alkenylenecarbonyl, arylene,heteroalkylene, heteroalkylenecarbonyl, heteroarylene,heteroarylenecarbonyl, heterocyclylalkylene, orheterocyclylalkylenecarbonyl.

In some cases, for a compound of Formula VIII, B is selected from a ringB structure listed in Table 3. In some cases, B is selected from B-I,B-I-2 to B-I-24, B-II, B-II-2 to B-II-52, B-III, B-III-2 to B-III-13,B-IV, B-IV-2 to B-IV-27, and any combination thereof. In some cases, Bis not one or more ring B structures listed in Table 3. In some cases, Bis not 1, 2, 3, 4, 5, 6, 7, or 8 ring B structures selected fromB-II-20, B-II-27, B-II-28, B-II-29, B-II-30, B-II-38, B-II-52, andB-III-13. In some cases, a ring B structure in Table 3 may contain oneor more R^(B) groups and may be optionally substituted with one or moreadditional R^(B) groups.

TABLE 3 Non-limiting examples of Ring B structures Ring B Number Ring BStructure B-I

B-I-2

B-I-3

B-I-4

B-I-5

B-I-6

B-I-7

B-I-8

B-I-9

B-I-10

B-I-11

B-I-12

B-I-13

B-I-14

B-I-15

B-I-16

B-I-17

B-I-18

B-I-19

B-I-20

B-I-21

B-I-22

B-I-23

B-I-24

B-II

B-II-2

B-II-3

B-II-4

B-II-5

B-II-6

B-II-7

B-II-8

B-II-9

B-II-10

B-II-11

B-II-12

B-II-13

B-II-14

B-II-15

B-II-16

B-II-17

B-II-18

B-II-19

B-II-20

B-II-21

B-II-22

B-II-23

B-II-24

B-II-25

B-II-26

B-II-27

B-II-28

B-II-29

B-II-30

B-II-31

B-II-32

B-II-33

B-II-34

B-II-35

B-II-36

B-II-37

B-II-38

B-II-39

B-II-40

B-II-41

B-II-42

B-II-43

B-II-44

B-II-45

B-II-46

B-II-47

B-II-48

B-II-49

B-II-50

B-II-51

B-II-52

B-III

B-III-2

B-III-3

B-III-4

B-III-5

B-III-6

B-III-7

B-III-8

B-III-9

B-III-10

B-III-11

B-III-12

B-III-13

B-IV

B-IV-2

B-IV-3

B-IV-4

B-IV-5

B-IV-6

B-IV-7

B-IV-8

B-IV-9

B-IV-10

B-IV-11

B-IV-12

B-IV-13

B-IV-14

B-IV-15

B-IV-16

B-IV-17

B-IV-18

B-IV-19

B-IV-20

B-IV-21

B-IV-22

B-IV-23

B-IV-24

B-IV-25

B-IV-26

B-IV-27

In certain embodiments, a compound of Formula VIII has an H-VIIIselected from an optionally substituted 5-membered heteroaryl, anoptionally substituted 6-membered aryl, and an optionally substituted6-membered heteroaryl. In some cases, ring carbons of H-VIII are, ateach occurrence, independently optionally substituted with R², R¹⁴, orR¹⁶. In some cases, ring nitrogens of H-VIII are, at each occurrence,independently optionally substituted with R¹⁵. In certain embodiments, acompound of Formula VIII has an H-VIII selected from an optionallysubstituted 5-membered heteroaryl and an optionally substituted6-membered heteroaryl.

In certain embodiments, the compound of Formula VIII has an H-VIIIselected from one of H-VIII-1 to H-VIII-21 in Table 1e. In particular,H-VIII may be selected from H-VIII-3 and H-VIII-13. In certainembodiments, H-VIII of a compound of Formula VIII is represented by theformula H-VIII-3:

wherein each of X¹, X², and X¹⁴ is independently selected from CR², N,NR¹⁵, O, and S; X¹¹ is selected from CR¹⁴, N, NR¹⁵, O, and S; and X¹³ isselected from a bond, CR¹⁶, and N, wherein when X¹³ is CR¹⁶ or N, theneach of X¹, X², and X¹⁴ is independently CR², N, or NR¹⁵ and X¹¹ isCR¹⁴, N, or NR¹⁵. In certain embodiments, H-VIII-3 contains 0, 1, 2, or3 ring heteroatoms. In certain embodiments, each of X¹, X², and X¹⁴ isindependently selected from CR², N, and NR¹⁵; X¹¹ is selected from CR¹⁴,N, and NR¹⁵; and X¹³ is selected from CR¹⁶ and N. In certainembodiments, up to one of X¹, X², X¹¹, and X¹⁴ is O or S. In certainembodiments, X¹ is CR²; X² is CR² or N; X¹¹ is N; X¹² is C; X¹³ is CR¹⁶;and X¹⁴ is CR². In certain embodiments, X¹⁴ is N, optionally wherein X¹and X¹³ are each CH. In certain embodiments, X² is CR², wherein R² isaralkyl, aryloxy or arylamino. Said aralkyl, aryloxy and arylamino maybe substituted with one or more substitutents selected from halo, alkyl,—C(═O)R_(g) and —C(═O)NR_(g)R_(h), wherein R_(g) and R_(h) areindependently hydrogen or alkyl. In certain embodiments, H-VIII has thestructure of H-VIII-10.

In certain embodiments, H-VIII of a compound of Formula VIII isrepresented by the formula H-VIII-13:

wherein each of X¹, X², and X¹⁴ is independently selected from CR², N,NR¹⁵, O, and S; X¹¹ is selected from CR¹⁴, N, NR¹⁵, O, and S; and X¹² isselected from C and N. In certain embodiments, H-VIII-13 contains 0, 1,or 2 ring heteroatoms. In certain embodiments, up to one of X¹, X², X¹¹,and X¹⁴ is O or S. In some cases, when X¹² is N, each of X¹, X², and X¹⁴is independently selected from CR², N, and NR¹⁵, and X¹¹ is selectedfrom CR¹⁴, N, and NR¹⁵.

In some cases, when H-VIII of Formula VIII is selected from anoptionally substituted 5-membered heteroaryl, an optionally substituted6-membered aryl, an optionally substituted 6-membered heteroaryl, andone of H-VIII-1 to H-VIII-21, such as from an optionally substituted5-membered heteroaryl, optionally substituted 6-membered heteroaryl,H-VIII-3, and H-VIII-13, R² of a compound of Formula VIII may be, ateach occurrence, selected from H, halo, hydroxyl, amino, cyano,dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, alkenyl,alkynyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl,alkoxy, and alkylamino, such as from H, halo, hydroxyl, amino, alkyl,heteroalkyl, and haloalkyl. In some cases, when H-VIII of Formula VIIIis selected from an optionally substituted 5-membered heteroaryl, anoptionally substituted 6-membered aryl, an optionally substituted6-membered heteroaryl, and one of H-VIII-1 to H-VIII-21, such as from anoptionally substituted 5-membered heteroaryl, optionally substituted6-membered heteroaryl, H-VIII-3, and H-VIII-13, R¹⁴, R¹⁵, and R¹⁶ of acompound of Formula VIII may be, at each occurrence, selected from H,halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl,amido, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, and alkylamino, such asfrom H, halo, hydroxyl, amino, alkyl, heteroalkyl, and haloalkyl.

In some cases, when H-VIII of Formula VIII is selected from anoptionally substituted 5-membered heteroaryl, an optionally substituted6-membered aryl, an optionally substituted 6-membered heteroaryl, andone of H-VIII-1 to H-VIII-21, such as from an optionally substituted5-membered heteroaryl, optionally substituted 6-membered heteroaryl,H-VIII-3, and H-VIII-13, L¹ may be selected from a bond, carbonyl, O, S,—NR⁵—, —NR⁶CH₂—, —NR⁶C(═O)—, —NR⁶SO₂—, C₁-C₄ alkylene, C₂-C₄ alkenylene,C₁-C₄ heteroalkylene, C₁-C₄ alkylenecarbonyl, C₂-C₄ alkenylenecarbonyl,and C₁-C₄ heteroalkylenecarbonyl. In particular, L¹ may be selected froma carbonyl, O, —NR⁵—, —NR⁶CH₂—, —NR⁶C(═O)—, —NR⁶SO₂—, C₁-C₄ alkylene,C₂-C₄ alkenylene, and C₁-C₄ heteroalkylene, such as —NR⁵— wherein R⁵ isselected from hydrogen and alkyl. L¹ may be —NH—.

In some cases, when H-VIII of Formula VIII is selected from anoptionally substituted 5-membered heteroaryl, an optionally substituted6-membered aryl, an optionally substituted 6-membered heteroaryl, andone of H-VIII-1 to H-VIII-21, such as from an optionally substituted5-membered heteroaryl, optionally substituted 6-membered heteroaryl,H-VIII-3, and H-VIII-13, Ring A may be selected from a 3-6 memberedring, such as from a 5-6 membered ring, such as from a 5-memberedcycloalkyl, 6-membered cycloalkyl, 5-membered heterocyclic ring,6-membered heterocyclic ring, 6-membered aryl, 5-membered heteroaryl,and 6-membered heteroaryl. In certain embodiments, A is a saturated 5-or 6-membered cycloalkyl or heterocyclic ring. In certain embodiments, Ais selected from A-1 to A-101. In certain embodiments, A is selectedfrom A-1 to A-18, A-40 to A-42, A-44, A-50 to A-57, A-78 to A-87, A-90,A-92, and A-95 to A-101. In certain embodiments, A is selected from A-1to A-18, A-41, A-44, A-57, and A-78 to A-87. In certain embodiments, Ais selected from A-1 to A-4, A-6 to A-9, A-11 to A-13, A-15 to A-17,A-41, A-44, A-57, and A-78 to A-87. In certain embodiments, A contains0, 1, or 2 ring N atoms. In certain embodiments, A contains 0, 1, or 2ring N atoms and no other ring heteroatoms. In certain embodiments, A isconnected at the same ring atom to L¹ and L². In certain embodiments, Ais connected at different ring atoms to L¹ and L². In certainembodiments, A is connected at a ring heteroatom to L¹ and/or L². Incertain embodiments, A is connected at a ring carbon to L¹ and/or L². Incertain embodiments, R^(A), at each occurrence, may be selected fromhalo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl,amido, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl,haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino,heterocyclylalkyl, and heteroarylalkyl. In certain embodiments, twoR^(A) groups attached to the same atom or different atoms may optionallyform a bridge or ring. In certain embodiments, m is 0 to 3.

In some cases, when H-VIII of Formula VIII is selected from anoptionally substituted 5-membered heteroaryl, an optionally substituted6-membered aryl, an optionally substituted 6-membered heteroaryl, andone of H-VIII-1 to H-VIII-21, such as from an optionally substituted5-membered heteroaryl, optionally substituted 6-membered heteroaryl,H-VIII-3, and H-VIII-13, L² may be selected from a bond, carbonyl, O, S,—NR⁵—, —NR⁶CH₂—, —NR⁶C(═O)—, —NR⁶SO₂—, C₁-C₄ alkylene, C₂-C₄ alkenylene,C₁-C₄ heteroalkylene, C₁-C₄ alkylenecarbonyl, C₂-C₄ alkenylenecarbonyl,and C₁-C₄ heteroalkylenecarbonyl, such as C₁-C₄ alkylene. In particular,L² may be selected from a carbonyl, O, —NR⁵—, —NR⁶CH₂—, —NR⁶C(═O)—,—NR⁶SO₂—, C₁-C₄ alkylene, and C₁-C₄ heteroalkylene.

In some cases, when H-VIII of Formula VIII is selected from anoptionally substituted 5-membered heteroaryl, an optionally substituted6-membered aryl, an optionally substituted 6-membered heteroaryl, andone of H-VIII-1 to H-VIII-21, such as from an optionally substituted5-membered heteroaryl, optionally substituted 6-membered heteroaryl,H-VIII-3, and H-VIII-13, Ring B may be selected from B-I, B-I-2 toB-I-24, B-II, B-II-2 to B-II-52, B-III, B-III-2 to B-III-13, B-IV, andB-IV-2 to B-IV-27, such as from indole, benzimidazole, benzoxazole, andimidazopyridine. In certain embodiments, B contains 0, 1, 2, 3, or 4ring heteroatoms, such as ring O and N atoms. In certain embodiments, Bcontains 0, 1, 2, 3, or 4 ring N atoms. In certain embodiments, Bcontains 0, 1, 2, 3, or 4 ring N atoms and no other ring heteroatoms. Incertain embodiments, B is connected at a ring heteroatom to L², such asa ring N atom. In certain embodiments, B is connected at a ring carbonto L², such as a ring carbon on an aromatic ring. In certainembodiments, R^(B), at each occurrence, may be selected from halo,hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido,acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, haloalkyl,aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, heterocyclylalkyl, andheteroarylalkyl. In certain embodiments, two R^(B) groups attached tothe same atom or different atoms may optionally form a bridge or ring.In certain embodiments, n is 0 to 4. In certain embodiments, n is 0 to2. In certain embodiments, n is 1, 2 or 3.

In some cases, when H-VIII of Formula VIII is selected from anoptionally substituted 5-membered heteroaryl, an optionally substituted6-membered aryl, an optionally substituted 6-membered heteroaryl, andone of H-VIII-1 to H-VIII-21, such as from an optionally substituted5-membered heteroaryl, optionally substituted 6-membered heteroaryl,H-VIII-3, and H-VIII-13, each of R², R⁷, R⁸, R¹⁰, R¹¹, R¹², R¹⁴, and R¹⁶is, at each occurrence, independently selected from H, halo, hydroxyl,amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl,heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino,cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino,cycloalkylalkylamino, heterocyclylalkyl, heterocyclyloxy,heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino,aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroarylalkyl,heteroaryloxy, heteroarylalkyloxy, heteroarylamino, andheteroarylalkylamino, such as from H, halo, hydroxyl, amino, cyano,dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, heteroalkyl,haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino,cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylalkylamino,heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino,aralkyl, aralkyloxy, aralkylamino, heteroarylalkyl, heteroarylalkyloxy,and heteroarylalkylamino. In some cases, each R² is independentlyselected from H, hydroxyl, amino, alkyl, haloalkyl, amido, cycloalkyl,aminoalkyl, aralkyl, aryloxy and arylamino. In some cases, H-VIII ofFormula VIII is H-VIII-10, wherein R² is independently selected from H,hydroxyl, amino, alkyl, haloalkyl, amido, cycloalkyl, aminoalkyl,aralkyl, aryloxy and arylamino.

In some cases, when H-VIII of Formula VIII is selected from anoptionally substituted 5-membered heteroaryl, an optionally substituted6-membered aryl, an optionally substituted 6-membered heteroaryl, andone of H-VIII-1 to H-VIII-21, such as from an optionally substituted5-membered heteroaryl, optionally substituted 6-membered heteroaryl,H-VIII-3, and H-VIII-13, each of R⁵, R⁶, R⁹, R¹³, and R¹⁵ is, at eachoccurrence, independently selected from H, acyl, alkyl, alkenyl,alkynyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,heteroaryl, and heteroarylalkyl, such as from H, acyl, alkyl,heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, cycloalkylalkyl,heterocyclylalkyl, aralkyl, and heteroarylalkyl.

In particular embodiments, H-VIII of Formula VIII is selected from anoptionally substituted 5-membered heteroaryl, optionally substituted6-membered heteroaryl, H-VIII-3, and H-VIII-13; L¹ is selected from O,—NR⁵—, —NR⁶CH₂—, —NR⁶C(═O)—, and —NR⁶SO₂—, such as from O and —NR⁵—; Ais selected from a 5- or 6-membered ring, such as from a cycloalkyl andheterocyclic ring; L² is selected from —NR⁵—, —NR⁶CH₂—, —NR⁶C(═O)—,—NR⁶SO₂—, C₁-C₄ alkylene, C₂-C₄ alkenylene, and C₁-C₄ heteroalkylene;and B is selected from B-I, B-I-2 to B-I-24, B-II, B-II-2 to B-II-52,B-III, B-III-2 to B-III-13, B-IV, and B-IV-2 to B-IV-27, such as fromindole, benzimidazole, benzoxazole, and imidazopyridine.

In certain embodiments, a compound of Formula VIII has the structure ofFormula VIII-A:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of X¹, X², and X¹⁴ is independently CR², N, NR¹⁵, O, or S;    -   X¹¹ is CR¹⁴, N, NR¹⁵, O, or S;    -   X¹² is C or N; and    -   X¹³ is a bond, CR¹⁶, or N, wherein when X¹³ is CR¹⁶ or N, then        each of X¹, X², and X¹⁴ is independently CR², N, or NR¹⁵ and X¹¹        is CR¹⁴, N, or NR¹⁵.

In certain embodiments, a compound of Formula VIII has the structure ofFormula VIII-B:

In certain embodiments, a compound of Formula VIII has the structure ofFormula VIII-C:

In certain embodiments, a compound of Formula VIII has the structure ofFormula VIII-D:

In certain embodiments, a compound of Formula VIII has the structure ofFormula VIII-E:

In certain embodiments, a compound of Formula VIII has the structure ofFormula VIII-F:

In certain embodiments, a compound of Formula VIII has the structure ofFormula VIII-G:

In certain embodiments, a compound of Formula VIII has the structure ofFormula VIII-H:

A compound of Formula VIII may be selected from any one of compoundsVIII-1 to VIII-79 listed in Table 4h. In certain embodiments, a compoundof Formula I is other than the structures listed in Table 4h.

TABLE 4h Exemplary compounds of Formula VIII Compound Number StructureVIII-1

VIII-2

VIII-3

VIII-4

VIII-5

VIII-6

VIII-7

VIII-8

VIII-9

VIII-10

VIII-11

VIII-12

VIII-13

VIII-14

VIII-15

VIII-16

VIII-17

VIII-18

VIII-19

VIII-20

VIII-21

VIII-22

VIII-23

VIII-24

VIII-25

VIII-26

VIII-27

VIII-28

VIII-29

VIII-30

VIII-31

VIII-32

VIII-33

VIII-34

VIII-35

VIII-36

VIII-37

VIII-38

VIII-39

VIII-40

VIII-41

VIII-42

VIII-43

VIII-44

VIII-45

VIII-46

VIII-47

VIII-48

VIII-49

VIII-50

VIII-51

VIII-52

VIII-53

VIII-54

VIII-55

VIII-56

VIII-57

VIII-58

VIII-59

VIII-60

VIII-61

VIII-62

VIII-63

VIII-64

VIII-65

VIII-66

VIII-67

VIII-68

VIII-69

VIII-70

VIII-71

VIII-72

VIII-73

VIII-74

VIII-75

VIII-76

VIII-77

VIII-78

VIII-79

VIII-80

VIII-81

VIII-82

VIII-83

VIII-84

VIII-85

VIII-86

VIII-87

VIII-88

VIII-89

VIII-90

VIII-91

VIII-92

VIII-93

VIII-94

VIII-95

VIII-96

VIII-97

VIII-98

VIII-99

VIII-100

VIII-101

VIII-102

VIII-103

VIII-104

VIII-105

VIII-106

VIII-107

VIII-108

VIII-109

VIII-110

VIII-111

VIII-112

VIII-113

VIII-114

VIII-115

VIII-116

VIII-117

VIII-118

VIII-119

VIII-120

VIII-121

VIII-122

VIII-123

VIII-124

VIII-125

VIII-126

VIII-127

VIII-128

VIII-129

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, the compound comprises an R², R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R^(A), or R^(B), such as R² orR^(B), selected from:

-   -   wherein:    -   G is selected from a bond, alkylene, heteroalkylene, C₃₋₁₂        carbocycle, 3- to 12-membered heterocycle, and combinations        thereof, wherein G is optionally substituted with one or more        R³² groups;    -   V is absent or selected from a C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; wherein V is optionally substituted        with one or more R³² groups;    -   each of R²¹ and R³² is, at each occurrence, independently        selected from:        -   H, halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R², —C(O)R²⁰,            —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰,            —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰),            —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, and —CN;        -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is            independently optionally substituted at each occurrence with            one or more substituents selected from halogen, —OR²⁰,            —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,            —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂,            —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂,            —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₃₋₁₀ carbocycle, and 3- to            10-membered heterocycle; and        -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle;        -   wherein two R³² on the same carbon atom can come together to            form a C₃₋₁₀ carbocycle or 3- to 10-membered heterocycle;        -   wherein each C₃₋₁₀ carbocycle and 3- to 10-membered            heterocycle of R³² is independently optionally substituted            with one or more substituents selected from halogen, —OR²⁰,            —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,            —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂,            —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂,            —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl,            and C₂₋₆ alkynyl;    -   R²⁰ at each occurrence is independently selected from:        -   hydrogen;        -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is            independently optionally substituted at each occurrence with            one or more substituents selected from halogen, —OR³⁰,            —SR³⁰, —N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)R³⁰, —C(O)OR³⁰,            —C(O)N(R³⁰)₂, —OC(O)R³⁰, —S(O)₂R³⁰, —S(O)₂N(R³⁰)₂,            —N(R³⁰)S(O)₂R³, —NO₂, —P(O)(OR³⁰)₂, —P(O)(R³⁰)₂,            —OP(O)(OR³⁰)₂, and —CN; and        -   3- to 10-membered heterocycle and C₃₋₁₀ carbocycle; and    -   R³⁰ at each occurrence is independently selected from hydrogen,        C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, R²¹ is a moiety with 5 to 50 atoms, such as amoiety with 5 to 40 atoms.

In some embodiments, V is selected from a 3-8 membered saturated ring,3-8 membered unsaturated ring, 4-10 membered fused bicyclic ring, and5-11 membered spiro bicyclic ring. V may be optionally substituted withone or more R³² groups, such as with 1, 2, 3, 4, or 5 R³² groups. Insome embodiments, V is a 3-7 membered saturated ring, such as a 3-7membered cycloalkyl or 3-7 membered aromatic or non-aromaticheterocycle. In some embodiments, V is a 3-7 membered unsaturated ring,such as a 6 membered aryl, 5-6 membered heteroaryl, or 3-7 memberedcycloalkenyl.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, V is selected from a 3-8 membered saturatedring optionally substituted with one or more R³² groups. In someembodiments of a compound of Formula VIII or pharmaceutically acceptablesalts thereof, V is a 3-, 4-, 5-, 6- or 7-membered saturated carbocycle,any one of which is optionally substituted with one or more R³² groups.In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, V is selected from:

any one of which is optionally substituted with one or more R³² groups.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, V is a 4-, 5-, 6-, 7- or 8-membered saturatedheterocycle, any one of which is optionally substituted with one or moreR³² groups. In some embodiments of a compound of Formula VIII orpharmaceutically acceptable salts thereof, V is selected from azetidine,oxetane, piperidine, oxane, piperazine, pyrrolidine, tetrahydrofuran,thiolane, imidazolidine, morpholine, thiomorpholine, azepane, andhomopiperazine, any one of which is optionally substituted with one ormore R³² groups. In some embodiments of a compound of Formula VIII orpharmaceutically acceptable salts thereof, V is selected from:

any one of which is optionally substituted with one or more R³² groups.In some embodiments, V is azetidine, piperidine or piperazine,substituted with one or more R²¹ groups, wherein R²¹ is selected from—S(═O)₂R²⁰, —S(═O)₂N(R²⁰)₂, and —NR²⁰S(═O)₂R²⁰. In some embodiments, R²¹is selected from —S(═O)R²⁰, —S(═O)₂R²⁰, —S(═O)₂N(R²⁰)₂, —NR²⁰S(═O)₂R²⁰;and C₁₋₁₀ alkyl substituted with one or more substituents selected from—S(═O)R²⁰, —S(═O)₂R²⁰, —S(═O)₂N(R²⁰)₂, and —NR²⁰S(═O)₂R²⁰. In someembodiments, R²¹ is selected from —S(═O)R²⁰, —S(═O)₂R²⁰, —S(═O)₂N(R²⁰)₂,and —NR²⁰S(═O)₂R²⁰, such as R²¹ is selected from —S(═O)CH₃, —S(═O)₂CH₃,—S(═O)₂NH₂, —NHS(═O)₂CH₃, and —S(═O)₂NHCH₃.

In some embodiments, —V—R²¹ is selected from

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, V is a bicyclic heterocycle, optionallysubstituted with one or more R³² groups. In some embodiments of acompound of Formula VIII or pharmaceutically acceptable salts thereof, Vis selected from

any one of which is optionally substituted with one or more R³² groups.

In certain embodiments, V is a 4-10 membered fused bicyclic ring, suchas a 8-10 membered fused bicyclic ring. In certain embodiments, thefused bicyclic ring includes one or more heteroatoms such as one or moreatoms selected from N, O, and S. In certain embodiments, the fusedbicyclic ring includes two heteroatoms such as two nitrogen atoms. Eachof the rings of the fused bicyclic ring may be saturated or unsaturated.In particular embodiments, both rings of the fused bicyclic ring aresaturated. Non-limiting examples of V comprising a fused bicyclic ringinclude

In some embodiments, V is a 5-11 membered spiro bicyclic ring, such as a7-11 membered spiro bicyclic ring. In certain embodiments, the fusedbicyclic ring includes one or more heteroatoms such as one or more atomsselected from N, O, and S. In particular embodiments, the fused bicyclicring includes two heteroatoms such as two nitrogen atoms. Non-limitingexamples of V comprising a spiro bicyclic ring include

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, V is selected from an unsaturated, aromatic,or heteroaromatic ring, any one of which is optionally substituted withone or more R³² groups. In some embodiments of a compound of FormulaVIII or pharmaceutically acceptable salts thereof, V is selected fromphenyl, pyridine, pyrazine, pyrimidine, pyridazine, naphthalene,anthracene, quinoline, isoquinoline, quinoxaline, acridine, quinazoline,cinnoline, phthalazine, furan, dihydrofuran, thiophene,dihydrothiophene, imidazole, imidazoline, oxazole, oxazoline, pyrrole,dihydropyrrole, thiazole, dihydrothiazole, pyrazole, dihydropyrazole,isoxazole, dihydroisoxazole, isothiazole, dihydroisothiazole,benzofuran, isobenzofuran, indole, isoindole, benzothiophene,benzimidazole, purine, indazole, benzoxazole, benzisoxazole, andbenzothiazole, any one of which is optionally substituted with one ormore R³² groups. In some embodiments of a compound of Formula VIII orpharmaceutically acceptable salts thereof, V is phenyl, optionallysubstituted with one or more R³² groups. In some embodiments of acompound of Formula VIII or pharmaceutically acceptable salts thereof, Vis a heteroaromatic ring optionally substituted with one or more R³²groups. In some embodiments of a compound of Formula VIII orpharmaceutically acceptable salts thereof, V is selected from pyridine,pyrazine, pyrimidine, pyridazine, naphthalene, anthracene, quinoline,isoquinoline, quinoxaline, acridine, quinazoline, cinnoline,phthalazine, furan, thiophene, imidazole, oxazole, pyrrole, thiazole,pyrazole, isoxazole, isothiazole, benzofuran, isobenzofuran, indole,isoindole, benzothiophene, benzimidazole, purine, indazole, benzoxazole,benzisoxazole, and benzothiazole, any one of which is optionallysubstituted with one or more R³² groups. In some embodiments of acompound of Formula VIII or pharmaceutically acceptable salts thereof, Vis selected from

wherein any one of which is optionally substituted with one or more R³²groups.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, V is absent.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, G is a bond.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, G is alkylene optionally substituted with oneor more R³² groups.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, G is selected from methylene, ethylene,propylene, and butylene, any one of which is optionally substituted withone or more R³² groups. In some embodiments of a compound of FormulaVIII or pharmaceutically acceptable salts thereof, G is selected from:

wherein any one of which is optionally substituted with one or more R³²groups. In some embodiments, G is —CH₂CH(CH₃)—. In some embodiments, Gis selected from

In some embodiments, G is

In some embodiments, G is

In some embodiments, G comprises a stereocenter. In some embodiments,the stereocenter is in the R-configuration. In some embodiments, thestereocenter is in the S-configuration. In some embodiments, theR-isomer of G is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, 99.5%, or 99.9% excess over the S-isomer. In some embodiments, theS-isomer of G is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, 99.5%, or 99.9% excess over the R-isomer.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, G is a heteroalkylene optionally substitutedwith one or more R³² groups.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, G is a C₃₋₁₀ carbocycle or 3- to 10-memberedheterocycle, any one of which is optionally substituted with one or moreR³² groups.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, G is a saturated C₃₋₁₀ carbocycle or saturated3- to 10-membered heterocycle, any one of which is optionallysubstituted with one or more R³² groups.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, G is selected from:

wherein any one of which is optionally substituted with one or more R³²groups.

In some embodiments, a compound of Formula VIII has the structure ofFormula VIII-1, VIII-A1, VIII-B1, VIII-C1, VIII-D1, VIII-E1, VIII-F1,VIII-G1, or VIII-H1:

In some embodiments, a compound of Formula VIII has the structure ofFormula VIII-A2:

such as Formula VIII-A3:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of X¹ and X² is independently selected from CR², N, NR¹⁵,        O, and S;    -   X¹¹ is selected from CR¹⁴, N, NR¹⁵, O, and S;    -   X¹² is C or N;    -   X¹³ is a bond, CR¹⁶, Or N;    -   each of L¹, L² and L³ is independently a bond, carbonyl, O, S,        —NR⁵—, —NR⁶CH₂—, —NR⁶C(═O)—, —NR⁶SO₂—, alkylene, alkenylene,        heteroalkylene, alkylenecarbonyl, alkenylenecarbonyl, or        heteroalkylenecarbonyl;    -   A is a bond, a 3-7 membered saturated ring, or a 3-7 membered        unsaturated ring;    -   m is an integer from 0 to 12;    -   B is selected from B-I, B-II, B-III, and B-IV,    -   wherein B is connected at any ring atom to L²;    -   B-I is

-   -   B-II is

-   -   B-III is

-   -   B-IV is

-   -   each of Z¹, Z², Z³, and Z⁴ is independently CR⁷, N, or NR⁹;    -   Z⁵ is C or N;    -   each of Z⁶, Z⁷, and Z⁸ is independently CR⁸, N, NR⁹, O, or S;    -   each of Z⁹, Z¹⁰, and Z¹¹ is independently CR¹⁰, CR¹¹R¹², NR¹³,        O, or S;    -   n is an integer from 0 to 6;    -   q is an integer from 0 to 6;    -   each of R², R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵,        and R¹⁶ is, at each occurrence, independently selected from H,        halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo,        carboxyl, amido, acyl, alkyl, alkenyl, alkynyl, cycloalkyl,        heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy,        alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy,        cycloalkylamino, cycloalkylalkylamino, heterocyclyl,        heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy,        heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl,        aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl,        heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy,        heteroarylamino, and heteroarylalkylamino;    -   each of R^(A), R^(B), and R^(H2) is, at each occurrence,        independently selected from halo, hydroxyl, amino, cyano,        dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl,        alkenyl, alkynyl, cycloalkyl, heteroalkyl, haloalkyl,        aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl,        cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino,        cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl,        heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino,        heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy,        arylamino, aralkylamino, heteroaryl, heteroarylalkyl,        heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and        heteroarylalkylamino,    -   wherein two R^(A) groups, two R^(b) groups, or two R^(H2) groups        attached to the same atom or different atoms can together        optionally form a bridge or ring;    -   G is selected from a bond, alkylene, heteroalkylene, C₃₋₁₂        carbocycle, and 3- to 12-membered heterocycle, wherein G is        optionally substituted with one or more R³² groups;    -   V is absent or selected from a C₃₋₁₂ carbocycle, and 3- to        12-membered heterocycle; wherein V is optionally substituted        with one or more R³² groups;    -   each of R²¹ and R³² is, at each occurrence, independently        selected from:        -   H, halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R², —C(O)R²⁰,            —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰,            —S(O)₂N(R²⁰)₂, —N(R⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰),            —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, and —CN;        -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is            independently optionally substituted at each occurrence with            one or more substituents selected from halogen, —OR²⁰,            —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,            —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂,            —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂,            —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₃₋₁₀ carbocycle, and 3- to            10-membered heterocycle; and        -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle;        -   wherein two R³² on the same carbon atom can come together to            form a C₃₋₁₀ carbocycle or 3- to 10-membered heterocycle;        -   wherein each C₃₋₁₀ carbocycle and 3- to 10-membered            heterocycle of R³² is independently optionally substituted            with one or more substituents selected from halogen, —OR²⁰,            —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,            —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂,            —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂,            —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl,            and C₂₋₆ alkynyl;    -   R²⁰ at each occurrence is independently selected from:        -   hydrogen;        -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is            independently optionally substituted at each occurrence with            one or more substituents selected from halogen, —OR³⁰,            —SR³⁰, —N(R³⁰)₂, —N(R³⁰)C(O)R³⁰, —C(O)R³⁰, —C(O)OR³⁰,            —C(O)N(R³⁰)₂, —OC(O)R³⁰, —S(O)₂R³⁰, —S(O)₂N(R³⁰)₂,            —N(R³⁰)S(O)₂R³⁰, —NO₂, —P(O)(OR³⁰)₂, —P(O)(R³⁰)₂,            —OP(O)(OR³⁰)₂, and —CN; and        -   3- to 10-membered heterocycle and C₃₋₁₀ carbocycle; and    -   R³⁰ at each occurrence is independently selected from hydrogen,        C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of a compound of Formula VIII-A3, L³ is selectedform —O—, —S—, —NH— and —CH₂—. In some embodiments, R^(H2) is selectedfrom halo, amido and acyl. In some embodiments, R^(H2) is selected fromhalo, —C(O)R⁵², and —C(O)N(R⁵²)₂, wherein R⁵² is selected from hydrogenand C₁₋₁₀ alkyl. In some embodiments,

optionally further substituted with one or more R^(H2). In someembodiments,

In some embodiments, a compound of Formula VIII has the structure ofFormula VIII-A4:

such as

In some embodiments, L³ is selected from —O— and —NH—.

In some embodiments, the compound is selected from Table 4h.

In certain aspects, compounds of the disclosure covalently bond withmenin and inhibit the interaction of menin with MLL. Such bonding maylead to an increase in the affinity of the compound for menin, which isan advantageous property in many applications, including therapeutic anddiagnostic uses. In certain embodiments, the compounds of the disclosurecomprise electrophilic groups capable of reacting with a nucleophilicgroup present in a menin protein. Suitable electrophilic groups aredescribed throughout the application, while suitable nucleophilic groupsinclude, for example, cysteine moieties present in the binding domain ofa menin protein. Without wishing to be bound by theory, a cysteineresidue in the menin binding domain may react with the electrophilicgroup of a compound of the disclosure, leading to formation of aconjugate product. In certain embodiments, the compounds of thedisclosure are capable of covalently bonding to the cysteine residue atposition 329 of a menin isoform 2 (SEQ ID NO: 2) or cysteine 334 inmenin isoform 1 (SEQ ID NO: 1). In certain embodiments, the disclosureprovides a conjugate of a compound of the disclosure with a meninprotein. For example, the disclosure provides a conjugate of a compoundof the invention with menin, bound at the cysteine residue 329 of meninisoform 2 (SEQ ID NO: 2) or cysteine 334 in menin isoform 1 (SEQ ID NO:1).

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, one or more of R², R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R^(A), and R^(B), when present, comprisesa functional group that covalently reacts with one or more residues onmenin. In some embodiments of a compound provided herein, the functionalgroup covalently reacts with one or more cysteine residues on menin. Insome embodiments of a compound provided herein, the functional groupcovalently reacts with a cysteine on menin at position 329 relative toSEQ ID NO: 2 when optimally aligned or position 334 relative to SEQ IDNO: 1 when optimally aligned. In certain embodiments, the functionalgroup covalently reacts with one or more residues on menin selected fromcysteine 329, cysteine 241, and/or cysteine 230 on menin relative to SEQID NO: 2 when optimally aligned. In certain embodiments, the functionalgroup covalently reacts with cysteine 329 relative to SEQ ID NO: 2 whenoptimally aligned.

In certain embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, one or more of R², R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R^(A), and R^(B), when present, comprisesa moiety that covalently reacts with one or more residues on menin. Inparticular embodiments, one or more of R², R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R^(A), and R^(B), when present, comprises amoiety that covalently reacts with any one or more isoforms of menin,for example, isoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2) orisoform 3 (SEQ ID NO: 3) of menin. In certain embodiments, one or moreof R², R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R^(A), andR^(B), when present, comprises a moiety that covalently reacts withmenin, wherein the menin protein shares 60% or more, 70% or more, 75% ormore, 80% or more, 85% or more, 90% or more, 95% or more, or 99% or moresequence identity with isoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO:2) or isoform 3 (SEQ ID NO: 3).

In certain embodiments, for a compound or salt of Formula VIII, one ormore of R², R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R^(A), and R^(B), when present, comprises an electrophilic group that issusceptible to nucleophilic attack from a residue on menin. Included inthe present disclosure are all electrophilic moieties that are known byone of skill in the art to bind to nucleophilic residues, for example,any electrophilic moiety known to bind to cysteine residues. In certainembodiments, for a compound or salt of Formula VIII, one or more of R²,R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R^(A), and R^(B),when present, comprises a moiety other than an electrophile wherein themoiety is capable of binding or covalently reacting with a residue onmenin. In particular embodiments, for a compound or salt of FormulaVIII, one or more of R², R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R^(A), and R^(B), when present, comprises a moiety thatcovalently reacts with one or more cysteine residues on menin, forexample, one or more of cysteine 329, cysteine 241, and cysteine 230relative to SEQ ID NO: 2 when optimally aligned. In certain embodiments,one or more of R², R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵,R¹⁶, R^(A), and R^(B), when present, comprises a moiety that covalentlyreacts with cysteine 329 in menin isoform 2 (SEQ ID NO: 2) or cysteine334 in menin isoform 1 (SEQ ID NO: 1). In certain embodiments, acompound or salt of Formula VIII, is capable of (a) binding covalentlyto menin and (b) inhibiting the interation of menin and MLL.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, the compound is capable of (a) bindingcovalently to menin and (b) inhibiting the interation of menin and MLL.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, R²¹ comprises a functional group thatcovalently reacts with one or more residues on menin. In someembodiments of a compound provided herein, the functional groupcovalently reacts with one or more cysteine residues on menin. In someembodiments of a compound provided herein, the functional groupcovalently reacts with a cysteine on menin at position 329 relative toSEQ ID NO: 2 when optimally aligned or position 334 relative to SEQ IDNO: 1 when optimally aligned.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, R²¹ is a moiety comprising an alpha,beta-unsaturated carbonyl; an alpha, beta-unsaturated sulfonyl; anepoxide; an aldehyde; sulfonyl fluoride; a halomethylcarbonyl; adihalomethylcarbonyl; or a trihalomethylcarbonyl.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, R²¹ is selected from:

-   -   wherein:    -   L⁵ is selected from a bond; and C₁₋₆ alkylene, C₁₋₆        heteroalkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene, each of        which is independently optionally substituted with one or more        R³² groups;    -   R²² and R²³ are selected from        -   hydrogen, halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰,            —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰,            —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰),            —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, and —CN;        -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is            independently optionally substituted at each occurrence with            one or more substituents selected from halogen, —OR²⁰,            —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,            —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂,            —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂,            —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₃₋₁₀ carbocycle, and 3- to            10-membered heterocycle; and        -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle,        -   wherein each C₃₋₁₀ carbocycle and 3- to 10-membered            heterocycle of R²² and R²³ is independently optionally            substituted with one or more substituents selected from            halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰,            —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰,            —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰),            —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₁₋₆ alkyl,            C₂₋₆ alkenyl, and C₂₋₆ alkynyl; or R²² and R²³, together            with the carbon atoms to which they are attached, form a            carbocyclic ring;    -   R²⁴ is selected from:        -   hydrogen, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰,            —S(O)₂R²⁰, and —S(O)₂N(R²⁰)₂;        -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is            independently optionally substituted at each occurrence with            one or more substituents selected from halogen, —OR²⁰,            —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,            —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂,            —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂,            —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₃₋₁₀ carbocycle, and 3- to            10-membered heterocycle; and        -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle,        -   wherein each C₃₋₁₀ carbocycle and 3- to 10-membered            heterocycle of R²⁴ is independently optionally substituted            with one or more substituents selected from halogen, —OR²⁰,            —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,            —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂,            —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂,            —P(O)(R²⁰)₂, —OP(O)(R²⁰)₂, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl,            and C₂₋₆ alkynyl.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, L⁵ is a bond. In some embodiments of acompound of Formula VIII or pharmaceutically acceptable salts thereof,L⁵ is optionally substituted C₁₋₆ alkylene. In some embodiments of acompound of Formula VIII or pharmaceutically acceptable salts thereof,L⁵ is selected from methylene, ethylene or propylene. In someembodiments of a compound of Formula VIII or pharmaceutically acceptablesalts thereof, L⁵ is substituted with one or more substituents selectedfrom halogen, —NO₂, ═O, ═S, —OR²⁰, —SR²⁰, and —N(R²⁰)₂.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, R²³ is selected from:

-   -   hydrogen;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —OR²⁰, —SR²⁰,        —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂,        —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O,        ═S, ═N(R²⁰), —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN,        C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle; and    -   C₃₋₁₀ carbocycle, and 3- to 10-membered heterocycle,    -   wherein each C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle        is independently optionally substituted with one or more        substituents selected from halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂,        —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰,        —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S,        ═N(R²⁰), —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₁₋₆        alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, R²³ is selected from:

-   -   hydrogen;    -   C₁₋₆ alkyl optionally substituted with one or more substituents        selected from halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂, ═O, ═S, ═N(R²⁰),        and —CN; and 3- to 10-membered heterocycle optionally        substituted with one or more substituents selected from halogen,        —OR²⁰, —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,        —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂,        —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂,        —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, and        C₂₋₆ alkynyl.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, R²³ is selected from hydrogen and C₁₋₆ alkyloptionally substituted with one or more substituents selected fromhalogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂, ═O, ═S, ═N(R²⁰), and —CN.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, R²² is selected from:

-   -   hydrogen and —CN;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —OR²⁰, —SR²⁰,        —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂,        —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O,        ═S, ═N(R²⁰), —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN,        C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle; and    -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle,    -   wherein each C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle        is independently optionally substituted with one or more        substituents selected from halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂,        —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰,        —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S,        ═N(R²⁰), —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₁₋₆        alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, R²² is selected from hydrogen; —CN; and C₁₋₆alkyl optionally substituted with one or more substituents selected fromhalogen, —OR²⁰, —SR²⁰, and —N(R²⁰)₂.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, R²² and R²³, together with the carbon atoms towhich they are attached, form a 5-, 6-, or 7-membered carbocyclic ring.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, R²⁴ is selected from hydrogen and C₁₋₆ alkyloptionally substituted with one or more substituents selected fromhalogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂, —NO₂, ═O, and —CN.

In some embodiments of a compound of Formula VIII or pharmaceuticallyacceptable salts thereof, R²¹ is selected from:

Pharmaceutical Compositions

The compositions and methods of the present invention may be utilized totreat an individual in need thereof. In certain embodiments, theindividual is a mammal such as a human, or a non-human mammal. Whenadministered to an animal, such as a human, the composition or thecompound is preferably administered as a pharmaceutical compositioncomprising, for example, a compound of Formula VIII or pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition is formulated fororal administration. In other embodiments, the pharmaceuticalcomposition is formulated for injection. In still more embodiments, thepharmaceutical compositions comprise a compound as disclosed herein andan additional therapeutic agent (e.g., anticancer agent). Non-limitingexamples of such therapeutic agents are described herein below.

Suitable routes of administration include, but are not limited to, oral,intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a composition of a compound of Formula VIII orpharmaceutically acceptable salt thereof is administered in a localrather than systemic manner, for example, via injection of the compounddirectly into an organ, often in a depot preparation or sustainedrelease formulation. In specific embodiments, long acting formulationsare administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Furthermore, in otherembodiments, a compound of Formula VIII or pharmaceutically acceptablesalt thereof is delivered in a targeted drug delivery system, forexample, in a liposome coated with organ-specific antibody. In suchembodiments, the liposomes are targeted to and taken up selectively bythe organ. In yet other embodiments, the composition is provided in theform of a rapid release formulation, in the form of an extended releaseformulation, or in the form of an intermediate release formulation. Inyet other embodiments, the composition is administered topically.

The compounds of Formula VIII or pharmaceutically acceptable saltthereof may be effective over a wide dosage range. For example, in thetreatment of adult humans, dosages from 0.01 to 1000 mg per day, from0.5 to 100 mg per day, from 1 to 50 mg per day, and from 5 to 40 mg perday are examples of dosages that may be used in some embodiments. Theexact dosage will depend upon the route of administration, the form inwhich the compound is administered, the subject to be treated, the bodyweight of the subject to be treated, and the preference and experienceof the attending physician.

In some embodiments, a compound of Formula VIII or pharmaceuticallyacceptable salt thereof is administered in a single dose. Typically,such administration will be by injection, e.g., intravenous injection,in order to introduce the agent quickly. However, other routes are usedas appropriate. In some embodiments, a single dose of a compound ofFormula VIII or pharmaceutically acceptable salt thereof is used fortreatment of an acute condition.

In some embodiments, a compound of Formula VIII or pharmaceuticallyacceptable salt thereof is administered in multiple doses. In someembodiments, dosing is about once, twice, three times, four times, fivetimes, six times, or more than six times per day. In other embodiments,dosing is about once a month, once every two weeks, once a week, or onceevery other day. In another embodiment, a compound of Formula VIII orpharmaceutically acceptable salt thereof and another agent areadministered together about once per day to about 6 times per day. Inanother embodiment, the administration of a compound of Formula VIII orpharmaceutically acceptable salt thereof and an agent continues for lessthan about 7 days. In yet another embodiment, the administrationcontinues for more than about 6 days, more than about 10 days, more thanabout 14 days, more than about 28 days, more than about two months, morethan about six months, or one year or more. In some cases, continuousdosing is achieved and maintained as long as necessary.

Administration of the compounds of Formula VIII or pharmaceuticallyacceptable salt thereof may continue as long as necessary. In someembodiments, a compound of the invention is administered for more than1, more than 2, more than 3, more than 4, more than 5, more than 6, morethan 7, more than 14, or more than 28 days. In some embodiments, acompound of the invention is administered 28 days or less, 14 days orless, 7 days or less, 6 days or less, 5 days or less, 4 days or less, 3days or less, 2 days or less, or 1 day or a part thereof. In someembodiments, a compound of Formula VIII or pharmaceutically acceptablesalt thereof is administered chronically on an ongoing basis, e.g., forthe treatment of chronic effects.

In some embodiments, the compounds of Formula VIII or pharmaceuticallyacceptable salt thereof are administered in dosages. It is known in theart that due to intersubject variability in compound pharmacokinetics,individualization of dosing regimen is necessary for optimal therapy.Dosing for a compound of Formula VIII or pharmaceutically acceptablesalt thereof may be found by routine experimentation in light of theinstant disclosure.

In some embodiments, the compound of Formula VIII or pharmaceuticallyacceptable salt thereof are formulated into pharmaceutical compositions.In specific embodiments, pharmaceutical compositions are formulated in aconventional manner using one or more physiologically acceptablecarriers comprising excipients and auxiliaries which facilitateprocessing of the active compounds into preparations which can be usedpharmaceutically. Proper formulation is dependent upon the route ofadministration chosen. Any pharmaceutically acceptable techniques,carriers, and excipients are used as suitable to formulate thepharmaceutical compositions described herein: Remington: The Science andPractice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack PublishingCompany, 1995); Hoover, John E., Remington's Pharmaceutical Sciences,Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L.,Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980;and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.(Lippincott Williams & Wilkins 1999).

Provided herein are pharmaceutical compositions comprising a compound ofFormula VIII or pharmaceutically acceptable salt thereof and apharmaceutically acceptable diluent(s), excipient(s), or carrier(s). Incertain embodiments, the compounds or salts described are administeredas pharmaceutical compositions in which a compound of Formula VIII orpharmaceutically acceptable salt thereof is mixed with other activeingredients, as in combination therapy. Encompassed herein are allcombinations of actives set forth in the combination therapies sectionbelow and throughout this disclosure. In specific embodiments, thepharmaceutical compositions include one or more compounds of FormulaVIII or pharmaceutically acceptable salt thereof.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula VIII or pharmaceutically acceptable salt thereofwith other chemical components, such as carriers, stabilizers, diluents,dispersing agents, suspending agents, thickening agents, and/orexcipients. In certain embodiments, the pharmaceutical compositionfacilitates administration of the compound to an organism. In someembodiments, practicing the methods of treatment or use provided herein,therapeutically effective amounts of compounds of Formula VIII orpharmaceutically acceptable salt thereof are administered in apharmaceutical composition to a mammal having a disease, disorder ormedical condition to be treated. In specific embodiments, the mammal isa human. In certain embodiments, therapeutically effective amounts varydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Thecompounds of Formula VIII or pharmaceutically acceptable salt thereofare used singly or in combination with one or more therapeutic agents ascomponents of mixtures.

In one embodiment, one or more compounds of Formula VIII orpharmaceutically acceptable salt thereof are formulated in an aqueoussolution. In specific embodiments, the aqueous solution is selectedfrom, by way of example only, a physiologically compatible buffer, suchas Hank's solution, Ringer's solution, or physiological saline buffer.In other embodiments, one or more compounds of Formula VIII orpharmaceutically acceptable salt thereof are formulated for transmucosaladministration. In specific embodiments, transmucosal formulationsinclude penetrants that are appropriate to the barrier to be permeated.In still other embodiments wherein the compounds of Formula VIII orpharmaceutically acceptable salt thereof are formulated for otherparenteral injections, appropriate formulations include aqueous ornonaqueous solutions. In specific embodiments, such solutions includephysiologically compatible buffers and/or excipients.

In another embodiment, compounds of Formula VIII or pharmaceuticallyacceptable salt thereof are formulated for oral administration.Compounds of Formula VIII or pharmaceutically acceptable salt thereofare formulated by combining the active compounds with, e.g.,pharmaceutically acceptable carriers or excipients. In variousembodiments, the compounds of Formula VIII or pharmaceuticallyacceptable salt thereof are formulated in oral dosage forms thatinclude, by way of example only, tablets, powders, pills, dragees,capsules, liquids, gels, syrups, elixirs, slurries, suspensions and thelike.

In certain embodiments, pharmaceutical preparations for oral use areobtained by mixing one or more solid excipient with one or more of thecompounds of Formula VIII or pharmaceutically acceptable salt thereof,optionally grinding the resulting mixture, and processing the mixture ofgranules, after adding suitable auxiliaries, if desired, to obtaintablets or dragee cores. Suitable excipients are, in particular, fillerssuch as sugars, including lactose, sucrose, mannitol, or sorbitol;cellulose preparations such as: for example, maize starch, wheat starch,rice starch, potato starch, gelatin, gum tragacanth, methylcellulose,microcrystalline cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP orpovidone) or calcium phosphate. In specific embodiments, disintegratingagents are optionally added. Disintegrating agents include, by way ofexample only, cross-linked croscarmellose sodium, polyvinylpyrrolidone,agar, or alginic acid or a salt thereof such as sodium alginate.

In one embodiment, dosage forms, such as dragee cores and tablets, areprovided with one or more suitable coating. In specific embodiments,concentrated sugar solutions are used for coating the dosage form. Thesugar solutions, optionally contain additional components, such as byway of example only, gum arabic, talc, polyvinylpyrrolidone, carbopolgel, polyethylene glycol, and/or titanium dioxide, lacquer solutions,and suitable organic solvents or solvent mixtures. Dyestuffs and/orpigments are also optionally added to the coatings for identificationpurposes. Additionally, the dyestuffs and/or pigments are optionallyutilized to characterize different combinations of active compounddoses.

In certain embodiments, therapeutically effective amounts of at leastone of the compounds of Formula VIII or pharmaceutically acceptable saltthereof are formulated into other oral dosage forms. Oral dosage formsinclude push-fit capsules made of gelatin, as well as soft, sealedcapsules made of gelatin and a plasticizer, such as glycerol orsorbitol. In specific embodiments, push-fit capsules contain the activeingredients in admixture with one or more filler. Fillers include, byway of example only, lactose, binders such as starches, and/orlubricants such as talc or magnesium stearate and, optionally,stabilizers. In other embodiments, soft capsules, contain one or moreactive compound that is dissolved or suspended in a suitable liquid.Suitable liquids include, by way of example only, one or more fatty oil,liquid paraffin, or liquid polyethylene glycol. In addition, stabilizersare optionally added.

In other embodiments, therapeutically effective amounts of at least oneof the compounds of Formula VIII or pharmaceutically acceptable saltthereof are formulated for buccal or sublingual administration.Formulations suitable for buccal or sublingual administration include,by way of example only, tablets, lozenges, or gels. In still otherembodiments, the compounds of Formula VIII or pharmaceuticallyacceptable salt thereof are formulated for parental injection, includingformulations suitable for bolus injection or continuous infusion. Inspecific embodiments, formulations for injection are presented in unitdosage form (e.g., in ampoules) or in multi-dose containers.Preservatives are, optionally, added to the injection formulations. Instill other embodiments, the pharmaceutical compositions are formulatedin a form suitable for parenteral injection as sterile suspensions,solutions or emulsions in oily or aqueous vehicles. Parenteral injectionformulations optionally contain formulatory agents such as suspending,stabilizing and/or dispersing agents. In specific embodiments,pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form. Inadditional embodiments, suspensions of of Formula VIII orpharmaceutically acceptable salt thereof are prepared as appropriateoily injection suspensions. Suitable lipophilic solvents or vehicles foruse in the pharmaceutical compositions described herein include, by wayof example only, fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. In certainspecific embodiments, aqueous injection suspensions contain substanceswhich increase the viscosity of the suspension, such as sodiumcarboxymethyl cellulose, sorbitol, or dextran. Optionally, thesuspension contains suitable stabilizers or agents which increase thesolubility of the compounds to allow for the preparation of highlyconcentrated solutions. In certain embodiments, the active agent is inpowder form for constitution with a suitable vehicle, e.g., sterilepyrogen-free water, before use.

In still other embodiments, the compounds of Formula VIII orpharmaceutically acceptable salt thereof are administered topically. Thecompounds of Formula VIII or pharmaceutically acceptable salt thereofmay be formulated into a variety of topically administrablecompositions, such as solutions, suspensions, lotions, gels, pastes,medicated sticks, balms, creams or ointments. Such pharmaceuticalcompositions optionally contain solubilizers, stabilizers, tonicityenhancing agents, buffers and preservatives.

In yet other embodiments, the compounds of Formula VIII orpharmaceutically acceptable salt thereof are formulated for transdermaladministration. Transdermal formulations may employ transdermal deliverydevices and transdermal delivery patches and can be lipophilic emulsionsor buffered, aqueous solutions, dissolved and/or dispersed in a polymeror an adhesive. In various embodiments, such patches are constructed forcontinuous, pulsatile, or on demand delivery of pharmaceutical agents.In additional embodiments, the transdermal delivery of the compounds ofFormula VIII or pharmaceutically acceptable salts thereof isaccomplished by means of iontophoretic patches and the like. In certainembodiments, transdermal patches provide controlled delivery of thecompounds of Formula VIII or pharmaceutically acceptable salt thereof.In specific embodiments, the rate of absorption is slowed by usingrate-controlling membranes or by trapping the compound within a polymermatrix or gel. In alternative embodiments, absorption enhancers are usedto increase absorption. Absorption enhancers or carriers includeabsorbable pharmaceutically acceptable solvents that assist passagethrough the skin. For example, in one embodiment, transdermal devicesare in the form of a bandage comprising a backing member, a reservoircontaining the compound of Formula VIII or pharmaceutically acceptablesalt thereof optionally with carriers, optionally a rate controllingbarrier to deliver the compound to the skin of the host at a controlledand predetermined rate over a prolonged period of time, and means tosecure the device to the skin.

In other embodiments, the compounds of Formula VIII or pharmaceuticallyacceptable salt thereof are formulated for administration by inhalation.Various forms suitable for administration by inhalation include, but arenot limited to, aerosols, mists or powders. Pharmaceutical compositionsof a compound of Formula VIII or pharmaceutically acceptable saltthereof are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebuliser, with the use of asuitable propellant (e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas). In specific embodiments, the dosage unit of apressurized aerosol is determined by providing a valve to deliver ametered amount. In certain embodiments, capsules and cartridges of, suchas, by way of example only, gelatin for use in an inhaler or insufflatorare formulated containing a powder mix of the compound of Formula VIIIor pharmaceutically acceptable salt thereof and a suitable powder basesuch as lactose or starch.

In still other embodiments, the compounds of Formula VIII orpharmaceutically acceptable salt thereof are formulated in rectalcompositions such as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas, containingconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and thelike. In suppository forms of the compositions, a low-melting wax suchas, but not limited to, a mixture of fatty acid glycerides, optionallyin combination with cocoa butter is first melted.

In certain embodiments, pharmaceutical compositions are formulated inany conventional manner using one or more physiologically acceptablecarriers comprising excipients and auxiliaries which facilitateprocessing of the active compounds into preparations which can be usedpharmaceutically. Proper formulation is dependent upon the route ofadministration chosen. Any pharmaceutically acceptable techniques,carriers, and excipients may be optionally used as suitable.Pharmaceutical compositions comprising a compound of Formula VIII orpharmaceutically acceptable salt thereof are manufactured in aconventional manner, such as, by way of example only, by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or compression processes.

Pharmaceutical compositions include at least one pharmaceuticallyacceptable carrier, diluent or excipient and at least one compound ofFormula VIII or pharmaceutically acceptable salt thereof, sometimesreferred to herein as an active agent or ingredient. The activeingredient may be in free-acid or free-base form, or in apharmaceutically acceptable salt form. Additionally, the compounds ofFormula VIII or pharmaceutically acceptable salt thereof may be inunsolvated or solvated forms with pharmaceutically acceptable solventssuch as water and ethanol. In addition, the pharmaceutical compositionsoptionally include other medicinal or pharmaceutical agents, carriers,adjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressure,buffers, and/or other therapeutically valuable substances.

Methods for the preparation of compositions comprising the compounds ofFormula VIII or pharmaceutically acceptable salt thereof includeformulating the compounds with one or more inert, pharmaceuticallyacceptable excipients or carriers to form a solid, semi-solid or liquid.Solid compositions include, but are not limited to, powders, tablets,dispersible granules, capsules, cachets, and suppositories. Liquidcompositions include solutions in which a compound is dissolved,emulsions comprising a compound, or a solution containing liposomes,micelles, or nanoparticles comprising a compound of Formula VIII orpharmaceutically acceptable salt thereof. Semi-solid compositionsinclude, but are not limited to, gels, suspensions and creams. The formof the pharmaceutical compositions of Formula VIII or pharmaceuticallyacceptable salt thereof include liquid solutions or suspensions, solidforms suitable for solution or suspension in a liquid prior to use, oras emulsions. These compositions also optionally contain minor amountsof nontoxic, auxiliary substances, such as wetting or emulsifyingagents, pH buffering agents, and so forth.

In some embodiments, pharmaceutical composition comprising at least onecompound of Formula VIII or pharmaceutically acceptable salt thereofillustratively takes the form of a liquid where the agents are presentin solution, in suspension or both. Typically when the composition isadministered as a solution or suspension a first portion of the agent ispresent in solution and a second portion of the agent is present inparticulate form, in suspension in a liquid matrix. In some embodiments,a liquid composition includes a gel formulation. In other embodiments,the liquid composition is aqueous.

In certain embodiments, aqueous suspensions contain one or more polymersas suspending agents. Polymers include water-soluble polymers such ascellulosic polymers, e.g., hydroxypropyl methylcellulose, andwater-insoluble polymers such as cross-linked carboxyl-containingpolymers. Certain pharmaceutical compositions described herein comprisea mucoadhesive polymer, selected for example fromcarboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

Pharmaceutical compositions also, optionally, include solubilizingagents to aid in the solubility of a compound described herein. The term“solubilizing agent” generally includes agents that result in formationof a micellar solution or a true solution of the agent. Certainacceptable nonionic surfactants, for example polysorbate 80, are usefulas solubilizing agents, as can ophthalmically acceptable glycols,polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

Pharmaceutical compositions optionally include one or more pH adjustingagents or buffering agents, including acids such as acetic, boric,citric, lactic, phosphoric and hydrochloric acids; bases such as sodiumhydroxide, sodium phosphate, sodium borate, sodium citrate, sodiumacetate, sodium lactate and tris-hydroxymethylaminomethane; and bufferssuch as citrate/dextrose, sodium bicarbonate and ammonium chloride. Suchacids, bases and buffers are included in an amount required to maintainpH of the composition in an acceptable range.

Additionally, useful compositions also, optionally, include one or moresalts in an amount required to bring osmolality of the composition intoan acceptable range. Such salts include those having sodium, potassiumor ammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

Pharmaceutical compositions optionally include one or more preservativesto inhibit microbial activity. Suitable preservatives includemercury-containing substances such as merfen and thiomersal; stabilizedchlorine dioxide; and quaternary ammonium compounds such as benzalkoniumchloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

Pharmaceutical compositions may include one or more surfactants toenhance physical stability or for other purposes. Suitable nonionicsurfactants include polyoxyethylene fatty acid glycerides and vegetableoils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40.

Pharmaceutical compositions may include one or more antioxidants toenhance chemical stability where required. Suitable antioxidantsinclude, by way of example only, ascorbic acid and sodium metabisulfite.

In certain embodiments, aqueous suspension compositions are packaged insingle-dose non-reclosable containers. Alternatively, multiple-dosereclosable containers are used, in which case it is typical to include apreservative in the composition.

In certain embodiments, delivery systems for hydrophobic pharmaceuticalcompounds are employed. Liposomes and emulsions are examples of deliveryvehicles or carriers useful herein. In certain embodiments, organicsolvents such as N-methylpyrrolidone are also employed. In additionalembodiments, the compounds of Formula VIII or pharmaceuticallyacceptable salt thereof are delivered using a sustained-release system,such as semipermeable matrices of solid hydrophobic polymers containingthe therapeutic agent. Various sustained-release materials may be usedherein. In some embodiments, sustained-release capsules release thecompounds for a few weeks up to over 100 days. Depending on the chemicalnature and the biological stability of the therapeutic reagent,additional strategies for protein stabilization are employed.

In certain embodiments, the formulations described herein comprise oneor more antioxidants, metal chelating agents, thiol containing compoundsand/or other general stabilizing agents. Examples of such stabilizingagents, include, but are not limited to: (a) about 0.5% to about 2% w/vglycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% toabout 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e)about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/vpolysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h)arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l)pentosan polysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

In some embodiments, the concentration of one or more compounds ofFormula VIII or pharmaceutically acceptable salt thereof provided in apharmaceutical compositions is less than about: 100%, 90%, 80%, 70%,60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%,10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%,0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%,0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%,0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or0.0001% w/w, w/v or v/v.

In some embodiments, the concentration of one or more compounds ofFormula VIII or pharmaceutically acceptable salt thereof provided in apharmaceutical composition is greater than about: 90%, 80%, 70%, 60%,50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25%18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%,15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%,10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%,7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%,4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%,2%, 1.75%, 1.50%, 1.25%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%,0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%,0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%,0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w,w/v, or v/v.

In some embodiments, the concentration of one or more compounds ofFormula VIII or pharmaceutically acceptable salt thereof is in the rangefrom approximately 0.0001% to approximately 50%, approximately 0.001% toapproximately 40%, approximately 0.01% to approximately 30%,approximately 0.02% to approximately 29%, approximately 0.03% toapproximately 28%, approximately 0.04% to approximately 27%,approximately 0.05% to approximately 26%, approximately 0.06% toapproximately 25%, approximately 0.07% to approximately 24%,approximately 0.08% to approximately 23%, approximately 0.09% toapproximately 22%, approximately 0.1% to approximately 21%,approximately 0.2% to approximately 20%, approximately 0.3% toapproximately 19%, approximately 0.4% to approximately 18%,approximately 0.5% to approximately 17%, approximately 0.6% toapproximately 16%, approximately 0.7% to approximately 15%,approximately 0.8% to approximately 14%, approximately 0.9% toapproximately 12%, approximately 1% to approximately 10% w/w, w/v orv/v.

In some embodiments, the concentration of one or more compounds ofFormula VIII or pharmaceutically acceptable salt thereof is in the rangefrom approximately 0.001% to approximately 10%, approximately 0.01% toapproximately 5%, approximately 0.02% to approximately 4.5%,approximately 0.03% to approximately 4%, approximately 0.04% toapproximately 3.5%, approximately 0.05% to approximately 3%,approximately 0.06% to approximately 2.5%, approximately 0.07% toapproximately 2%, approximately 0.08% to approximately 1.5%,approximately 0.09% to approximately 1%, approximately 0.1% toapproximately 0.9% w/w, w/v or v/v.

In some embodiments, the amount of one or more compounds of Formula VIIIor pharmaceutically acceptable salt thereof is equal to or less thanabout: 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g,0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g,0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g,0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g,0.0002 g, or 0.0001 g.

In some embodiments, the amount of one or more compounds of Formula VIIIor pharmaceutically acceptable salt thereof is more than about: 0.0001g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g,0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g,0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g,0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g,0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or10 g.

In some embodiments, the amount of one or more compounds of Formula VIIIor pharmaceutically acceptable salt thereof is in the range of 0.0001-10g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4g, or 1-3 g.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also provided. In some embodiments, suchkits comprise a carrier, package, or container that is compartmentalizedto receive one or more containers such as vials, tubes, and the like,each of the container(s) comprising one of the separate elements to beused in a method described herein. Suitable containers include, forexample, bottles, vials, syringes, and test tubes. The containers areformed from a variety of materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products includethose found in, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, bottles, and any packaging material suitable for aselected formulation and intended mode of administration and treatment.For example, the container(s) includes one or more compounds of FormulaVIII or pharmaceutically acceptable salt thereof, optionally in acomposition or in combination with another agent as disclosed herein.The container(s) optionally have a sterile access port (for example thecontainer is an intravenous solution bag or a vial having a stopperpierceable by a hypodermic injection needle). Such kits optionallycomprising a compound with an identifying description or label orinstructions relating to its use in the methods described herein.

For example, a kit typically includes one or more additional containers,each with one or more of various materials (such as reagents, optionallyin concentrated form, and/or devices) desirable from a commercial anduser standpoint for use of a compound described herein. Non-limitingexamples of such materials include, but not limited to, buffers,diluents, filters, needles, syringes; carrier, package, container, vialand/or tube labels listing contents and/or instructions for use, andpackage inserts with instructions for use. A set of instructions willalso typically be included. A label is optionally on or associated withthe container. For example, a label is on a container when letters,numbers or other characters forming the label are attached, molded oretched into the container itself, a label is associated with a containerwhen it is present within a receptacle or carrier that also holds thecontainer, e.g., as a package insert. In addition, a label is used toindicate that the contents are to be used for a specific therapeuticapplication. In addition, the label indicates directions for use of thecontents, such as in the methods described herein. In certainembodiments, the pharmaceutical composition is presented in a pack ordispenser device which contains one or more unit dosage forms containinga compound provided herein. The pack, for example, contains metal orplastic foil, such as a blister pack. Or, the pack or dispenser deviceis accompanied by instructions for administration. Or, the pack ordispenser is accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, is the labeling approved bythe U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. In some embodiments, compositions containing acompound provided herein formulated in a compatible pharmaceuticalcarrier are prepared, placed in an appropriate container, and labeledfor treatment of an indicated condition.

Methods

The present invention provides a method of inhibiting the interaction ofmenin and one or more proteins (e.g., MLL1, MLL2, a MLL fusion protein,or a MLL Partial Tandem Duplication) comprising contacting a cell withan effective amount of one or more compounds of Formula VIII orpharmaceutically acceptable salt thereof. Inhibition of the interactionof menin and one or more proteins (e.g., MLL1, MLL2, a MLL fusionprotein, or a MLL Partial Tandem Duplication) can be assessed anddemonstrated by a wide variety of ways known in the art. Non-limitingexamples include a showing of (a) a decrease in menin binding to one ormore proteins or protein fragments (e.g., MLL1, MLL2, a MLL fusionprotein, a MLL Partial Tandem Duplication, or a peptide fragmentthereof); (b) a decrease in cell proliferation and/or cell viability;(c) an increase in cell differentiation; (d) a decrease in the levels ofdownstream targets of MLL1, MLL2, a MLL fusion protein, and/or a MLLPartial Tandem Duplication (e.g., Hoxa9, DLX2, and Meis1); and/or (e)decrease in tumor volume and/or tumor volume growth rate. Kits andcommercially available assays can be utilized for determining one ormore of the above.

The invention also provides methods of using the compounds orpharmaceutical compositions of the present invention to treat diseaseconditions, including but not limited to conditions implicated by menin,MLL, MLL1, MLL2, and/or MLL fusion proteins (e.g., cancer).

In some embodiments, a method for treatment of cancer is provided, themethod comprising administering an effective amount of any of theforegoing pharmaceutical compositions comprising a compound of FormulaVIII or pharmaceutically acceptable salt thereof to a subject in needthereof. In some embodiments, the cancer is mediated by a MLL fusionprotein. In other embodiments, the cancer is leukemia, breast cancer,prostate cancer, pancreatic cancer, lung cancer, liver cancer, skincancer, or a brain tumor. In certain embodiments, the cancer isleukemia. In some embodiments, the cancer comprises a solid tumor.

In some embodiments the invention provides method of treating a disorderin a subject in need thereof, wherein the the method comprisesdetermining if the subject has a MLL fusion protein and if the subjectis determined to have a MLL fusion protein, then administering to thesubject a therapeutically effective dose of at least one compound ofFormula VIII or a pharmaceutically acceptable salt, ester, or prodrugthereof.

MLL fusion proteins have also been identified in hematologicalmalignancies (e.g., cancers that affect blood, bone marrow and/or lymphnodes). Accordingly, certain embodiments are directed to administrationof a compound of Formula VIII to a patient in need of treatment of ahematological malignancy. Such malignancies include, but are not limitedto leukemias and lymphomas. For example, the presently disclosedcompounds can be used for treatment of diseases such as Acutelymphoblastic leukemia (ALL), Acute myelogenous leukemia (AML), Chroniclymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Chronicmyelogenous leukemia (CML), Acute monocytic leukemia (AMoL), hairy cellleukemia, and/or other leukemias. In other embodiments, the compoundscan be used for treatment of lymphomas such as all subtypes of Hodgkinslymphoma or non-Hodgkins lymphoma.

Determining whether a tumor or cancer comprises a MLL fusion protein canbe undertaken by assessing the nucleotide sequence encoding the MLLfusion protein, by assessing the amino acid sequence of the MLL fusionprotein, or by assessing the characteristics of a putative MLL fusionprotein.

Methods for detecting a MLL fusion protein nucleotide sequence are knownby those of skill in the art. These methods include, but are not limitedto, polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) assays, polymerase chain reaction-single strand conformationpolymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing,mutant allele-specific PCR amplification (MASA) assays, directsequencing, primer extension reactions, electrophoresis, oligonucleotideligation assays, hybridization assays, TaqMan assays, SNP genotypingassays, high resolution melting assays and microarray analyses. In someembodiments, the MLL fusion protein is identified using a directsequencing method of specific regions (e.g., exon 2 and/or exon 3) inthe MLL or fusion partner gene, for example. This technique willidentify all possible mutations in the region sequenced.

Methods for detecting a MLL fusion protein are known by those of skillin the art. These methods include, but are not limited to, detection ofa MLL fusion protein using a binding agent (e.g., an antibody) specificfor the fusion protein, protein electrophoresis and Western blotting,and direct peptide sequencing.

Methods for determining whether a tumor or cancer comprises a MLL fusionprotein can use a variety of samples. In some embodiments, the sample istaken from a subject having a tumor or cancer. In some embodiments, thesample is taken from a subject having a cancer or tumor. In someembodiments, the sample is a fresh tumor/cancer sample. In someembodiments, the sample is a frozen tumor/cancer sample. In someembodiments, the sample is a formalin-fixed paraffin-embedded sample. Insome embodiments, the sample is processed to a cell lysate. In someembodiments, the sample is processed to DNA or RNA.

The invention also relates to a method of treating a hyperproliferativedisorder in a mammal that comprises administering to the mammal atherapeutically effective amount of a compound of Formula VIII or apharmaceutically acceptable salt, ester, or prodrug thereof. In someembodiments, the method relates to the treatment of cancer such as acutemyeloid leukemia, cancer in adolescents, adrenocortical carcinomachildhood, AIDS-related cancers (e.g., Lymphoma and Kaposi's Sarcoma),anal cancer, appendix cancer, astrocytomas, atypical teratoid, basalcell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumors, burkittlymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germcell tumor, primary lymphoma, cervical cancer, childhood cancers,chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronicmyelogenous leukemia (CML), chronic myleoproliferative disorders, coloncancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma,extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNScancer, endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor,extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone,gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumors (GIST), germ cell tumor, gestationaltrophoblastic tumor, hairy cell leukemia, head and neck cancer, heartcancer, liver cancer, hodgkin lymphoma, hypopharyngeal cancer,intraocular melanoma, islet cell tumors, pancreatic neuroendocrinetumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer,liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma,metastatic squamous neck cancer with occult primary, midline tractcarcinoma, mouth cancer, multiple endocrine neoplasia syndromes,multiple myeloma/plasma cell neoplasm, mycosis fungoides,myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms,multiple myeloma, merkel cell carcinoma, malignant mesothelioma,malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavityand paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma,non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer,lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer,pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus andnasal cavity cancer, parathyroid cancer, penile cancer, pharyngealcancer, pleuropulmonary blastoma, primary central nervous system (CNS)lymphoma, prostate cancer, rectal cancer, transitional cell cancer,retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer,stomach (gastric) cancer, small cell lung cancer, small intestinecancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throatcancer, thymoma and thymic carcinoma, thyroid cancer, transitional cellcancer of the renal pelvis and ureter, trophoblastic tumor, unusualcancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer,vulvar cancer, or Viral-Induced cancer. In some embodiments, the methodrelates to the treatment of a non-cancerous hyperproliferative disordersuch as benign hyperplasia of the skin (e.g., psoriasis), restenosis, orprostate (e.g., benign prostatic hypertrophy (BPH)). In some cases, themethod relates to the treatment of leukemia, hematologic malignancy,solid tumor cancer, prostate cancer (e.g., castration-resistant prostatecancer), breast cancer, Ewing's sarcoma, bone sarcoma, primary bonesarcoma, T-cell prolymphocyte leukemia, glioma, glioblastoma, livercancer (e.g., hepatocellular carcinoma), or diabetes. In some cases, theleukemia comprises AML, ALL, Mixed Lineage Leukemia or leukemias withPartial Tandem Duplications of MLL.

In certain particular embodiments, the invention relates to methods fortreatment of lung cancers, the methods comprise administering aneffective amount of any of the above described compound (or apharmaceutical composition comprising the same) to a subject in needthereof. In certain embodiments the lung cancer is a non-small cell lungcarcinoma (NSCLC), for example adenocarcinoma, squamous-cell lungcarcinoma or large-cell lung carcinoma. In other embodiments, the lungcancer is a small cell lung carcinoma. Other lung cancers treatable withthe disclosed compounds include, but are not limited to, glandulartumors, carcinoid tumors and undifferentiated carcinomas.

Subjects that can be treated with compounds of the invention, orpharmaceutically acceptable salt, ester, prodrug, solvate, tautomer,stereoisomer, isotopologue, hydrate or derivative of the compounds,according to the methods of this invention include, for example,subjects that have been diagnosed as having acute myeloid leukemia,acute myeloid leukemia, cancer in adolescents, adrenocortical carcinomachildhood, AIDS-related cancers (e.g., Lymphoma and Kaposi's Sarcoma),anal cancer, appendix cancer, astrocytomas, atypical teratoid, basalcell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumors, burkittlymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germcell tumor, primary lymphoma, cervical cancer, childhood cancers,chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronicmyelogenous leukemia (CML), chronic myleoproliferative disorders, coloncancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma,extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNScancer, endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor,extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone,gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumors (GIST), germ cell tumor, gestationaltrophoblastic tumor, hairy cell leukemia, head and neck cancer, heartcancer, liver cancer, hodgkin lymphoma, hypopharyngeal cancer,intraocular melanoma, islet cell tumors, pancreatic neuroendocrinetumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer,liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma,metastatic squamous neck cancer with occult primary, midline tractcarcinoma, mouth cancer, multiple endocrine neoplasia syndromes,multiple myeloma/plasma cell neoplasm, mycosis fungoides,myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms,multiple myeloma, merkel cell carcinoma, malignant mesothelioma,malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavityand paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma,non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer,lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer,pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus andnasal cavity cancer, parathyroid cancer, penile cancer, pharyngealcancer, pleuropulmonary blastoma, primary central nervous system (CNS)lymphoma, prostate cancer, rectal cancer, transitional cell cancer,retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer,stomach (gastric) cancer, small cell lung cancer, small intestinecancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throatcancer, thymoma and thymic carcinoma, thyroid cancer, transitional cellcancer of the renal pelvis and ureter, trophoblastic tumor, unusualcancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer,vulvar cancer, Viral-Induced cancer, leukemia, hematologic malignancy,solid tumor cancer, prostate cancer, castration-resistant prostatecancer, breast cancer, Ewing's sarcoma, bone sarcoma, primary bonesarcoma, T-cell prolymphocyte leukemia, glioma, glioblastoma,hepatocellular carcinoma, liver cancer, or diabetes. In some embodimentssubjects that are treated with the compounds of the invention includesubjects that have been diagnosed as having a non-canceroushyperproliferative disorder such as benign hyperplasia of the skin(e.g., psoriasis), restenosis, or prostate (e.g., benign prostatichypertrophy (BPH)).

The invention further provides methods of modulating the interaction ofmenin and one or more proteins (e.g., MLL1, MLL2, a MLL fusion protein,or a MLL Partial Tandem Duplication) by contacting the menin with aneffective amount of a compound of Formula VIII or pharmaceuticallyacceptable salt thereof. Modulation can be inhibiting or activatingprotein activity of menin, one or more of its binding partners, and/orone or more of the downstream targets of menin or one or more of itsbinding partners. In some embodiments, the invention provides methods ofinhibiting the interaction of menin and one or more proteins (e.g.,MLL1, MLL2, a MLL fusion protein, or a MLL Partial Tandem Duplication)by contacting menin with an effective amount of a compound of FormulaVIII or pharmaceutically acceptable salt thereof. In some embodiments,the invention provides methods of inhibiting the interaction of meninand one or more proteins (e.g., MLL1, MLL2, a MLL fusion protein, or aMLL Partial Tandem Duplication) by contacting a cell, tissue, or organthat expresses menin, MLL1, MLL2, a MLL fusion protein, and/or a MLLPartial Tandem Duplication. In some embodiments, the invention providesmethods of inhibiting protein activity in subject including but notlimited to rodents and mammal (e.g., human) by administering into thesubject an effective amount of a compound of Formula VIII orpharmaceutically acceptable salt thereof. In some embodiments, thepercentage modulation exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.In some embodiments, the percentage of inhibiting exceeds 25%, 30%, 40%,50%, 60%, 70%, 80%, or 90%.

In some embodiments, the invention provides methods of inhibiting theinteraction of menin and one or more proteins (e.g., MLL1, MLL2, a MLLfusion protein, or a MLL Partial Tandem Duplication) in a cell bycontacting the cell with an amount of a compound of the inventionsufficient to inhibit the interaction of menin and one or more proteins(e.g., MLL1, MLL2, a MLL fusion protein, or a MLL Partial TandemDuplication) in the cell. In some embodiments, the invention providesmethods of inhibiting the interaction of menin and one or more proteins(e.g., MLL1, MLL2, a MLL fusion protein, or a MLL Partial TandemDuplication) in a tissue by contacting the tissue with an amount of acompound of Formula VIII or pharmaceutically acceptable salt thereofsufficient to inhibit the interaction of menin and one or more proteins(e.g., MLL1, MLL2, a MLL fusion protein, or a MLL Partial TandemDuplication) in the tissue. In some embodiments, the invention providesmethods of inhibiting the interaction of menin and one or more proteins(e.g., MLL1, MLL2, a MLL fusion protein, or a MLL Partial TandemDuplication) in an organism by contacting the organism with an amount ofa compound of Formula VIII or pharmaceutically acceptable salt thereofsufficient to inhibit the interaction of menin and one or more proteins(e.g., MLL1, MLL2, a MLL fusion protein, or a MLL Partial TandemDuplication) in the organism. In some embodiments, the inventionprovides methods of inhibiting the interaction of menin and one or moreproteins (e.g., MLL1, MLL2, a MLL fusion protein, or a MLL PartialTandem Duplication) in an animal by contacting the animal with an amountof a compound of the invention sufficient to inhibit the interaction ofmenin and one or more proteins (e.g., MLL1, MLL2, a MLL fusion protein,or a MLL Partial Tandem Duplication) in the animal. In some embodiments,the invention provides methods of inhibiting the interaction of meninand one or more proteins (e.g., MLL1, MLL2, a MLL fusion protein, or aMLL Partial Tandem Duplication) in a mammal by contacting the mammalwith an amount of a compound of the invention sufficient to inhibit theinteraction of menin and one or more proteins (e.g., MLL1, MLL2, a MLLfusion protein, or a MLL Partial Tandem Duplication) in the mammal. Insome embodiments, the invention provides methods of inhibiting theinteraction of menin and one or more proteins (e.g., MLL1, MLL2, a MLLfusion protein, or a MLL Partial Tandem Duplication) in a human bycontacting the human with an amount of a compound of the inventionsufficient to inhibit the interaction of menin and one or more proteins(e.g., MLL1, MLL2, a MLL fusion protein, or a MLL Partial TandemDuplication) in the human. The present invention provides methods oftreating a disease mediated by the interaction of menin and one or moreproteins (e.g., MLL1, MLL2, a MLL fusion protein, or a MLL PartialTandem Duplication) in a subject in need of such treatment.

The invention further provides methods of stabilizing menin, comprisingcontacting menin with a compound of Formula VIII or pharmaceuticallyacceptable salts thereof. In some embodiments, the contacting stepcomprises contacting menin with an amount of the compound sufficient tostabilize menin. In some embodiments, the contacting step takes place invivo. In some embodiments, the contacting step takes place in vitro. Insome embodiments, the contacting step takes place in a cell.

The invention also provides methods of treating a disorder mediated bymenin interaction with one or more proteins (e.g., MLL1, MLL2, a MLLfusion protein, or a MLL Partial Tandem Duplication) by administering toa subject in need thereof a therapeutically effective amount of acompound of Formula VIII or pharmaceutically acceptable salt thereof.

The invention further provides methods of treating a disorder mediatedby chromosomal rearrangement on chromosome 11q23 in a subject in needthereof by administering to the subject a therapeutically effectiveamount of a compound of Formula VIII or pharmaceutically acceptable saltthereof.

The invention also provides methods for the treatment of a disease orcondition by administering an effective amount of a compound of FormulaVIII or pharmaceutically acceptable salt thereof to a subject sufferingfrom the disease or condition.

The invention further provides methods for the treatment of a disease orcondition by administering a compound of Formula VIII orpharmaceutically acceptable salt thereof to a subject suffering from thedisease or condition, wherein the compound binds to menin and inhibitsthe interaction of menin with one or more proteins (e.g., MLL1, MLL2, aMLL fusion protein, or a MLL Partial Tandem Duplication).

The present invention also provides methods for combination therapies inwhich an agent known to modulate other pathways, or other components ofthe same pathway, or even overlapping sets of target enzymes are used incombination with a compound of Formula VIII or pharmaceuticallyacceptable salt thereof. In one aspect, such therapy includes but is notlimited to the combination of one or more compounds of the inventionwith chemotherapeutic agents, therapeutic antibodies, and radiationtreatment, to provide a synergistic or additive therapeutic effect.

Where desired, the compounds or pharmaceutical composition of thepresent invention can be used in combination with Notch inhibitorsand/or c-Myb inhibitors. Where desired, the compounds or pharmaceuticalcomposition of the present invention can be used in combination withMLL-WDR5 inhibitors and/or Dot11 inhibitors.

Many chemotherapeutics are presently known in the art and can be used incombination with the compounds of the invention. In some embodiments,the chemotherapeutic is selected from the group consisting of mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, anti-hormones,angiogenesis inhibitors, and anti-androgens.

Non-limiting examples are chemotherapeutic agents, cytotoxic agents, andnon-peptide small molecules such as Gleevec® (Imatinib Mesylate),Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), andAdriamycin as well as a host of chemotherapeutic agents. Non-limitingexamples of chemotherapeutic agents include alkylating agents such asthiotepa and cyclosphosphamide (CYTOXAN™); alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; nitrogenmustards such as chlorambucil, chlornaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine,bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin,carzinophilin, Casodex™, chromomycins, dactinomycin, daunorubicin,detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin,esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid,nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformithine; elliptinium acetate; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone;mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.,paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, N.J.) anddocetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoicacid; esperamicins; capecitabine; and pharmaceutically acceptable salts,acids or derivatives of any of the above. Also included as suitablechemotherapeutic cell conditioners are anti-hormonal agents that act toregulate or inhibit hormone action on tumors such as anti-estrogensincluding for example tamoxifen, (Nolvadex™), raloxifene, aromataseinhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene,LY 117018, onapristone, and toremifene (Fareston); and anti-androgenssuch as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin;chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate;platinum analogs such as cisplatin and carboplatin; vinblastine;platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone;vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin;aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11);topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO). Wheredesired, the compounds or pharmaceutical composition of the presentinvention can be used in combination with commonly prescribedanti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®,Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridinecarboxamide, Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin,Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehydethiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins,Antineoplastic, Antitumorigenic herbs, Apaziquone, Atiprimod,Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar,Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy),Calyculin, cell-cycle nonspecific antineoplastic agents, Dichloroaceticacid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin,Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICEchemotherapy regimen, IT-101, Imexon, Imiquimod, Indolocarbazole,Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan,Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel,PAC-1, Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin,Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, StanfordV, Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar,Tesetaxel, Triplatin tetranitrate, Tris(2-chloroethyl)amine,Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126 or Zosuquidar.

This invention further relates to a method for using the compounds ofFormula VIII or pharmaceutically acceptable salt thereof orpharmaceutical compositions provided herein, in combination withradiation therapy for inhibiting abnormal cell growth or treating thehyperproliferative disorder in the mammal. Techniques for administeringradiation therapy are known in the art, and these techniques can be usedin the combination therapy described herein. The administration of thecompound of the invention in this combination therapy can be determinedas described herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g., At-211,I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner of the present invention include both solids andliquids. By way of non-limiting example, the radiation source can be aradionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source,I-125 as a solid source, or other radionuclides that emit photons, betaparticles, gamma radiation, or other therapeutic rays. The radioactivematerial can also be a fluid made from any solution of radionuclide(s),e.g., a solution of I-125 or I-131, or a radioactive fluid can beproduced using a slurry of a suitable fluid containing small particlesof solid radionuclides, such as Au-198, Y-90. Moreover, theradionuclide(s) can be embodied in a gel or radioactive micro spheres.

The compounds or pharmaceutical compositions of the invention can beused in combination with an amount of one or more substances selectedfrom anti-angiogenesis agents, signal transduction inhibitors,antiproliferative agents, glycolysis inhibitors, or autophagyinhibitors.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-11(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound of the invention and pharmaceutical compositions describedherein. Anti-angiogenesis agents include, for example, rapamycin,temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, andbevacizumab. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172 (publishedOct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European PatentApplication No. 97304971.1 (filed Jul. 8, 1997), European PatentApplication No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (publishedFeb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16,1998), European Patent Publication 606,046 (published Jul. 13, 1994),European Patent Publication 931,788 (published Jul. 28, 1999), WO90/05719 (published May 31, 1990), WO 99/52910 (published Oct. 21,1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (publishedJun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filedJul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar.25, 1999), Great Britain Patent Application No. 9912961.1 (filed Jun. 3,1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12,1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No.5,861,510 (issued Jan. 19, 1999), and European Patent Publication780,386 (published Jun. 25, 1997), all of which are incorporated hereinin their entireties by reference. Preferred MMP-2 and MMP-9 inhibitorsare those that have little or no activity inhibiting MMP-1. Morepreferred, are those that selectively inhibit MMP-2 and/or AMP-9relative to the other matrix-metalloproteinases (e.g., MAP-1, MMP-3,MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).Some specific examples of MMP inhibitors useful in the invention areAG-3340, RO 32-3555, and RS 13-0830.

Autophagy inhibitors include, but are not limited to chloroquine,3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1,5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid,autophagy-suppressive algal toxins which inhibit protein phosphatases oftype 2A or type 1, analogues of cAMP, and drugs which elevate cAMPlevels such as adenosine, LY204002, N6-mercaptopurine riboside, andvinblastine. In addition, antisense or siRNA that inhibits expression ofproteins including but not limited to ATG5 (which are implicated inautophagy), may also be used.

In some embodiments, the compounds described herein are formulated oradministered in conjunction with liquid or solid tissue barriers alsoknown as lubricants. Examples of tissue barriers include, but are notlimited to, polysaccharides, polyglycans, seprafilm, interceed andhyaluronic acid.

In some embodiments, medicaments which are administered in conjunctionwith the compounds described herein include any suitable drugs usefullydelivered by inhalation for example, analgesics, e.g., codeine,dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations,e.g., diltiazem; antiallergics, e.g., cromoglycate, ketotifen ornedocromil; anti-infectives, e.g., cephalosporins, penicillins,streptomycin, sulphonamides, tetracyclines or pentamidine;antihistamines, e.g., methapyrilene; anti-inflammatories, e.g.,beclomethasone, flunisolide, budesonide, tipredane, triamcinoloneacetonide or fluticasone; antitussives, e.g., noscapine;bronchodilators, e.g., ephedrine, adrenaline, fenoterol, formoterol,isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutalin,isoetharine, tulobuterol, orciprenaline or(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol;diuretics, e.g., amiloride; anticholinergics e.g., ipratropium, atropineor oxitropium; hormones, e.g., cortisone, hydrocortisone orprednisolone; xanthines e.g., aminophylline, choline theophyllinate,lysine theophyllinate or theophylline; and therapeutic proteins andpeptides, e.g., insulin or glucagon. It will be clear to a personskilled in the art that, where appropriate, the medicaments are used inthe form of salts (e.g., as alkali metal or amine salts or as acidaddition salts) or as esters (e.g., lower alkyl esters) or as solvates(e.g., hydrates) to optimize the activity and/or stability of themedicament.

Other exemplary therapeutic agents useful for a combination therapyinclude but are not limited to agents as described above, radiationtherapy, hormone antagonists, hormones and their releasing factors,thyroid and antithyroid drugs, estrogens and progestins, androgens,adrenocorticotropic hormone; adrenocortical steroids and their syntheticanalogs; inhibitors of the synthesis and actions of adrenocorticalhormones, insulin, oral hypoglycemic agents, and the pharmacology of theendocrine pancreas, agents affecting calcification and bone turnover:calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitaminssuch as water-soluble vitamins, vitamin B complex, ascorbic acid,fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines,chemokines, muscarinic receptor agonists and antagonists;anticholinesterase agents; agents acting at the neuromuscular junctionand/or autonomic ganglia; catecholamines, sympathomimetic drugs, andadrenergic receptor agonists or antagonists; and 5-hydroxytryptamine(5-HT, serotonin) receptor agonists and antagonists.

Therapeutic agents can also include agents for pain and inflammationsuch as histamine and histamine antagonists, bradykinin and bradykininantagonists, 5-hydroxytryptamine (serotonin), lipid substances that aregenerated by biotransformation of the products of the selectivehydrolysis of membrane phospholipids, eicosanoids, prostaglandins,thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatoryagents, analgesic-antipyretic agents, agents that inhibit the synthesisof prostaglandins and thromboxanes, selective inhibitors of theinducible cyclooxygenase, selective inhibitors of the induciblecyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin,cytokines that mediate interactions involved in humoral and cellularimmune responses, lipid-derived autacoids, eicosanoids, P-adrenergicagonists, ipratropium, glucocorticoids, methylxanthines, sodium channelblockers, opioid receptor agonists, calcium channel blockers, membranestabilizers and leukotriene inhibitors.

Additional therapeutic agents contemplated herein include diuretics,vasopressin, agents affecting the renal conservation of water, rennin,angiotensin, agents useful in the treatment of myocardial ischemia,anti-hypertensive agents, angiotensin converting enzyme inhibitors,β-adrenergic receptor antagonists, agents for the treatment ofhypercholesterolemia, and agents for the treatment of dyslipidemia.

Other therapeutic agents contemplated include drugs used for control ofgastric acidity, agents for the treatment of peptic ulcers, agents forthe treatment of gastroesophageal reflux disease, prokinetic agents,antiemetics, agents used in irritable bowel syndrome, agents used fordiarrhea, agents used for constipation, agents used for inflammatorybowel disease, agents used for biliary disease, agents used forpancreatic disease. Therapeutic agents used to treat protozoaninfections, drugs used to treat Malaria, Amebiasis, Giardiasis,Trichomoniasis, Trypanosomiasis, and/or Leishmaniasis, and/or drugs usedin the chemotherapy of helminthiasis. Other therapeutic agents includeantimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazolequinolones, and agents for urinary tract infections, penicillins,cephalosporins, and other, β-lactam antibiotics, an agent comprising anaminoglycoside, protein synthesis inhibitors, drugs used in thechemotherapy of tuberculosis, Mycobacterium avium complex disease, andleprosy, antifungal agents, antiviral agents including nonretroviralagents and antiretroviral agents.

Examples of therapeutic antibodies that can be combined with a compoundof the invention include but are not limited to anti-receptor tyrosinekinase antibodies (cetuximab, panitumumab, trastuzumab), anti CD20antibodies (rituximab, tositumomab), and other antibodies such asalemtuzumab, bevacizumab, and gemtuzumab.

Moreover, therapeutic agents used for immunomodulation, such asimmunomodulators, immunosuppressive agents, tolerogens, andimmunostimulants are contemplated by the methods herein. In addition,therapeutic agents acting on the blood and the blood-forming organs,hematopoietic agents, growth factors, minerals, and vitamins,anticoagulant, thrombolytic, and antiplatelet drugs.

For treating renal carcinoma, one may combine a compound of the presentinvention with sorafenib and/or avastin. For treating an endometrialdisorder, one may combine a compound of the present invention withdoxorubincin, taxotere (taxol), and/or cisplatin (carboplatin). Fortreating ovarian cancer, one may combine a compound of the presentinvention with cisplatin (carboplatin), taxotere, doxorubincin,topotecan, and/or tamoxifen. For treating breast cancer, one may combinea compound of the present invention with taxotere (taxol), gemcitabine(capecitabine), tamoxifen, letrozole, tarceva, lapatinib, PD0325901,avastin, herceptin, OSI-906, and/or OSI-930. For treating lung cancer,one may combine a compound of the present invention with taxotere(taxol), gemcitabine, cisplatin, pemetrexed, Tarceva, PD0325901, and/oravastin.

Further therapeutic agents that can be combined with a compound of theinvention are found in Goodman and Gilman's “The Pharmacological Basisof Therapeutics” Tenth Edition edited by Hardman, Limbird and Gilman orthe Physician's Desk Reference, both of which are incorporated herein byreference in their entirety.

The compounds described herein can be used in combination with theagents disclosed herein or other suitable agents, depending on thecondition being treated. Hence, in some embodiments the one or morecompounds of the invention will be co-administered with other agents asdescribed above. When used in combination therapy, the compoundsdescribed herein are administered with the second agent simultaneouslyor separately. This administration in combination can includesimultaneous administration of the two agents in the same dosage form,simultaneous administration in separate dosage forms, and separateadministration. That is, a compound described herein and any of theagents described above can be formulated together in the same dosageform and administered simultaneously. Alternatively, a compound of theinvention and any of the agents described above can be simultaneouslyadministered, wherein both the agents are present in separateformulations. In another alternative, a compound of the presentinvention can be administered just followed by and any of the agentsdescribed above, or vice versa. In some embodiments of the separateadministration protocol, a compound of the invention and any of theagents described above are administered a few minutes apart, or a fewhours apart, or a few days apart.

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples, andthroughout the specification and claims, molecules with a single chiralcenter, unless otherwise noted, exist as a racemic mixture. Thosemolecules with two or more chiral centers, unless otherwise noted, existas a racemic mixture of diastereomers. Single enantiomers/diastereomersmay be obtained by methods known to those skilled in the art.

Examples

Non-Limiting Examples of Compound Synthesis

Synthesis of a Compound of Formula VIII

Synthesis of a Compound of Formula VIII, Compound VIII-1

Synthesis of a Compound of Formula VIII

Synthesis of a Compound of Formula VIII, Compound VIII-27

Non-Limiting Examples of Experimental Assays

Fluorescence Polarization Assay.

This example illustrates an assay effective in monitoring the binding ofMLL to menin. Fluorescence polarization (FP) competition experiments areperformed to determine the effectiveness with which a compound inhibitsthe menin-MLL interaction, reported as an IC₅₀ value. Afluorescein-labeled 12-amino acid peptide containing the high affinitymenin binding motif found in MLL is produced according to Yokoyama etal. (Cell, 2005, 123(2): 207-218), herein incorporated by reference inits entirety. Binding of the labeled peptide (1.7 kDa) to the muchlarger menin (˜67 kDa) is accompanied by a significant change in therotational correlation time of the fluorophore, resulting in asubstantial increase in the fluorescence polarization and fluorescenceanisotropy (excitation at 500 nm, emission at 525 nm). The effectivenesswith which a compound inhibits the menin-MLL interaction is measured inan FP competition experiment, wherein a decrease in fluorescenceanisotropy correlates with inhibition of the interaction and is used asa read-out for IC₅₀ determination.

Homogeneous Time-Resolve Fluorescence (HTRF) Assay.

A homogeneous time-resolve fluorescence (HTRF) assay is utilized as asecondary assay to confirm the results of the FP assay. In someembodiments, the HTRF assay is the primary assay and the FP assay isused as a secondary assay to confirm results. HTRF is based on thenon-radiative energy transfer of the long-lived emission from theEuropium cryptate (Eu³⁺-cryptate) donor to the allophycocyanin (XL665)acceptor, combined with time-resolved detection. An Eu³⁺-cryptate donoris conjugated with mouse anti-6His monoclonal antibody (which bindsHis-tagged menin) and XL665-acceptor is conjugate to streptavidin (whichbinds biotinylated MLL peptide). When these two fluorophores are broughttogether by the interaction of menin with the MLL peptide, energytransfer to the acceptor results in an increase in fluorescence emissionat 665 nm and increased HTRF ratio (emission intensity at 665nm/emission intensity at 620 nm). Inhibition of the menin-MLLinteraction separates the donor from the acceptor, resulting in adecrease in emission at 665 nm and decreased HTRF ratio.

Menin Engagement Assay.

Sample Preparation: 2.5 μL of 100 μM compound is added to 47.5 μL of 526nM menin in PBS (5 μM compound 500 nM menin in 5% DMSO finalconcentration). Reaction is incubated at room temperature for variablelengths of time and quenched with 2.5 μL of 4% formic acid (FA, 0.2%final concentration). Method: A Thermo Finnigan Surveyor Autosampler,PDA Plus UV detector and MS Pump along with an LTQ linear ion trap massspectrometer are used to collect sample data under XCalibur softwarecontrol. A 5 μL sample in “no waste” mode is injected onto a PhenomenexJupiter 5 u 300A C5 (guard column) 2×4.00 mm at 45° C. Mobile phasecomposition: Buffer A (95:5 water:acetonitrile, 0.1% FA) and Buffer B(acetonitrile, 0.1% FA). Gradient elution is used with an initial mobilephase of 85:15 (Buffer A:B) and a flow rate of 250 μL/min. Uponinjection, 85:15 A:B is held for 1.3 min, Buffer B is increased to 90%over 3.2 min, held for 1 min, and then returned to initial conditions in0.1 min and held for 2.4 min. The total run time is 8 min. A post-columndivert valve employed to direct void volume salts to waste is used forthe first 2 min of the sample method. Blank injection of Buffer A isused in between each of the sample injections. A needle wash of 1:1acetonitrile:water with 0.1% FA is used. The electrospray ionization(ESI) source uses a 300° C. capillary temperature, 40 units sheath gasflow, 20 units aux gas flow, 3 units sweep gas flow, 3.5 kV sprayvoltage, and 120 V tube lens. Data Collection: Data collection isperformed in the positive ion full scan mode 550-1500 Da, 10 microscans,200 ms max ion time. Data analysis: Protein mass spectra are acquired asXCalibur datafiles. The best scans are added together using XCaliburQual Browser. The spectra are displayed using “View/Spectrum List with aDisplay option to display all peaks. The Edit/Copy cell menu is used tocopy the mass spectrum into the PC clipboard. The spectrum in the PCclipboard is pasted into Excel. The first two columns (m/z and Intensityare kept and the third column (Relative) is deleted. The remaining twocolumns are then saved as a tab delimited file (m/z and intensity) asfilename.txt from Excel. The Masslynx Databridge program is then used toconvert the filename.txt tab delimited file to Masslynx format. In somecases, an external calibration using a (similarly converted) myoglobinspectrum is applied in Masslynx to correct the m/z values of the meninprotein m/z data. MaxEntl software from the MassLynx software suite isused for deconvolution of the mass spectrum to yield the average MW ofthe protein(s). The percentage of covalent adduct formation isdetermined from the deconvoluted spectrum and used to calculate thereaction rate (k) of the covalent reaction.

Cell Proliferation Assay.

The ability of a compound of the present invention to inhibit the growthof cells, such as human leukemia, VCaP, LNCaP, 22RV1, DU145, LNCaP-AR,MV4;11, KOPN-8, ML-2, MOLM-13, bone marrow cells (BMCs), MLL-AF9,MLL-ENL, MLL-CBP, MLL-GAS7, MLL-AF1p, MLL-AF6, HM-2, E2A-HLF, HL-60 andNB4 cells, is tested using a cell viability assay, such as the PromegaCellTiter-Glo® Luminescent Cell Viability Assay (Promega TechnicalBulletin, 2015, “CellTiter-Glo® Luminescent Cell Viability Assay”: 1-15,herein incorporated by reference in its entirety). Cells are plated atrelevant concentrations, for example about 1×10⁵-2×10⁵ cells per well ina 96-well plate. A compound of the present invention is added at aconcentration up to about 2 μM with eight, 2-fold serial dilutions foreach compound. Cells are incubated at 37° C. for a period of time, forexample, 72 hours, then cells in the control wells are counted. Media ischanged to restore viable cell numbers to the original concentration,and compounds are re-supplied. Proliferation is measured about 72 hourslater using Promega CellTiter-Glo® reagents, as per kit instructions.

RT-PCR Analysis of MLL Fusion Protein Downstream Targets.

The effect of a compound of the present invention on expression of oneor more MLL fusion protein downstream targets is assessed by RT-PCR.Cells, such as VCaP, LNCaP, 22RV1, DU145, LNCaP-AR, MV4;11, KOPN-8,ML-2, MOLM-13, bone marrow cells (BMCs), MLL-AF9, MLL-ENL, MLL-CBP,MLL-GAS7, MLL-AF1p, MLL-AF6, HM-2, E2A-HLF, HL-60 and NB4 cells, aretreated with an effective concentration of a compound for about 7 daysor less, then total RNA is extracted from cells using an RNeasy mini kit(QIAGEN). Total RNA is reverse transcribed using a High Capacity cDNAReverse Transcription Kit (Applied Biosystems), and relativequantification of relevant gene transcripts (e.g., Hoxa9, DLX2, andMeis1) is determined by real-time PCR. Effective inhibition of themenin-MLL interaction is expected to result in the downregulation ofdownstream targets of MLL, including Hoxa9, DLX2, and Meis1.

Pharmacokinatic Studies in Mice.

The pharmacokinetics of menin-MLL inhibitors are determined in femaleC57BL/6 mice following intravenous (iv) dosing at 15 mg/kg and oraldosing (po) at 30 mg/kg. Compounds are dissolved in the vehiclecontaining 25% (v/v) DMSO, 25% (v/v) PEG-400 and 50% (v/v) PBS. Serialblood samples (50 μL) are collected over 24 h, centrifuged at 15,000 rpmfor 10 min and saved for analysis. Plasma concentrations of thecompounds are determined by the LC-MS/MS method developed and validatedfor this study. The LC-MS/MS method consists of an Agilent 1200 HPLCsystem and chromatographic separation of tested compound is achievedusing an Agilent Zorbax Extend-C18 column (5 cm×2.1 mm, 3.5 μm; Waters).An AB Sciex QTrap 3200 mass spectrometer equipped with an electrosprayionization source (ABI-Sciex, Toronto, Canada) in the positive-ionmultiple reaction monitoring (MRM) mode is used for detection. Allpharmacokinetic parameters are calculated by noncompartmental methodsusing WinNonlin® version 3.2 (Pharsight Corporation, Mountain View,Calif., USA).

Efficacy Study in Mouse Xenograft Tumor Model.

Immunodeficient mice, such as 8-10 week-old female nude (nu/nu) mice,are used for in vivo efficacy studies in accordance with the guidelinesapproved by IACUC. Leukemia cells, such as human MV4-11 leukemia cellsavailable from ATCC, are implanted subcutaneously via needle into femalenude mice (5×10⁶ cells/mouse). When the tumor reaches a size ofapproximately 150 to 250 mm³ in mice, the tumor-bearing mice arerandomly assigned to a vehicle control or compound treatment group (8animals per group). Animals are treated with a compound of the presentinvention by oral gavage or intraperitoneal injection in an appropriateamount and frequency as can be determined by the skilled artisan withoutundue experimentation. Subcutaneous tumor volume in nude mice and micebody weight are measured twice weekly. Tumor volumes are calculated bymeasuring two perpendicular diameters with calipers(V=(length×width²)/2). Percentage tumor growth inhibition (%TGI=1−[change of tumor volume in treatment group/change of tumor volumein control group]*100) is used to evaluate anti-tumor efficacy.Statistical significance is evaluated using a one-tailed, two sample ttest. P<0.05 is considered statistically significant.

Efficacy Study in Prostate Tumor Xenograft Model.

Immunodeficient mice, such as 4-6 week-old male CB17 severe combinedimmunodeficiency (SCID) mice, are used for in vivo efficacy studies inaccordance with the guidelines approved by IACUC. Parental prostatecancer cells, such as VCaP or LNCaP-AR cells, are implantedsubcutaneously into male CB. 17.SCID mice (3-4×10⁶ cells in 50%Matrigel). When the tumor reaches a palpable size of approximately 80mm³, the tumor-bearing mice are randomly assigned to a vehicle controlor compound treatment group (6 or more animals per group). Animals aretreated with a compound of the present invention by intraperitonealinjection in an appropriate amount and frequency as can be determined bythe skilled artisan without undue experimentation. In one example, miceare treated with 40 mg/kg of a compound of the present invention dailyby i.p. injection for two weeks, then 5 days per week thereafter.Subcutaneous tumor volume and mice body weight are measured twiceweekly. Tumor volumes are calculated by measuring two perpendiculardiameters with calipers (V=(length×width²)/2).

Efficacy Study in Castration-Resistant Prostate Tumor Xenograft Model(VCaP).

Immunodeficient mice, such as 4-6 week-old male CB17 severe combinedimmunodeficiency (SCID) mice, are used for in vivo efficacy studies inaccordance with the guidelines approved by IACUC. Parental prostatecancer cells, such as VCaP cells, are implanted subcutaneously into maleCB.17.SCID mice (3-4×10⁶ cells in 50% Matrigel). When the tumor reachesa size of approximately 200-300 mm³, the tumor-bearing mice arephysically castrated and tumors observed for regression and regrowth toapproximately 150 mm³. The tumor-bearing mice are randomly assigned to avehicle control or compound treatment group (6 or more animals pergroup). Animals are treated with a compound of the present invention byintraperitoneal injection in an appropriate amount and frequency as canbe determined by the skilled artisan without undue experimentation. Inone example, mice are treated with 40 mg/kg of a compound of the presentinvention daily by i.p. injection. Subcutaneous tumor volume and micebody weight are measured twice weekly. Tumor volumes are calculated bymeasuring two perpendicular diameters with calipers(V=(length×width²)/2).

Efficacy Study in Castration-Resistant Prostate Tumor Xenograft Model(LNCaP-AR).

Immunodeficient mice, such as 4-6 week-old male CB17 severe combinedimmunodeficiency (SCID) mice, are used for in vivo efficacy studies inaccordance with the guidelines approved by IACUC. CB.17.SCID mice aresurgically castrated and allowed to recover for 2-3 weeks beforeimplanting parental prostate cancer cells, such as LNCaP-AR cells,subcutaneously into (3-4×10⁶ cells in 50% Matrigel). When the tumorreaches a size of approximately 80-100 mm³, the tumor-bearing mice arerandomly assigned to a vehicle control or compound treatment group (6 ormore animals per group). Animals are treated with a compound of thepresent invention by intraperitoneal injection in an appropriate amountand frequency as can be determined by the skilled artisan without undueexperimentation. In one example, mice are treated with 60 mg/kg of acompound of the present invention daily by i.p. injection for 27 days.Subcutaneous tumor volume and mice body weight are measured twiceweekly. Tumor volumes are calculated by measuring two perpendiculardiameters with calipers (V=(length×width²)/2).

Cellular Thermal Shift Assay (CETSA).

For the cell lysate CETSA experiments, cultured cells from cell lines(e.g., HEK293, bone marrow samples) are harvested and washed with PBS.The cells are diluted in kinase buffer (KB) (25 mMTris(hydroxymethyl)-aminomethane hydrochloride (Tris-HCl, pH 7.5), 5 mMbeta-glycerophosphate, 2 mM dithiothreitol (DTT), 0.1 mM sodium vanadiumoxide, 10 mM magnesium chloride) or in phosphate-buffered saline (PBS)(10 mM phosphate buffer (pH 7.4), 2.7 mM potassium chloride and 137 mMsodium chloride). All buffers are supplemented with Complete proteaseinhibitor cocktail. The cell suspensions are freeze-thawed three timesusing liquid nitrogen. The soluble fraction (lysate) is separated fromthe cell debris by centrifugation at 20000×g for 20 minutes at 4° C. Thecell lysates are diluted with appropriate buffer and divided into twoaliquots, with one aliquot being treated with drug (e.g., compound ofany of Formulas I, II, III, IV, V, VI, IX, and X or pharmaceuticallyacceptable salts thereof) and the other aliquot with the diluent of theinhibitor (control). After 10-30 minute incubation at room temperaturethe respective lysates are divided into smaller (50 μL) aliquots andheated individually at different temperatures for 3 minutes followed bycooling for 3 minutes at room temperature. The appropriate temperaturesare determined in preliminary CETSA experiments. The heated lysates arecentrifuged at 20000×g for 20 minutes at 4° C. in order to separate thesoluble fractions from precipitates. The supernatants are transferred tonew microtubes and analyzed by sodium dodecyl sulfate polyacrylamide gelelectrophoresis (SDS-PAGE) followed by western blot analysis.

For the intact cell experiments the drug-treated cells from the in vitroexperiments above are heated as previously described followed byaddition of KB (30 μL) and lysed using 2 cycles of freeze-thawing withliquid nitrogen. The soluble fractions are isolated and analyzed bywestern blot.

For the in vivo mice experiments, lysates of frozen tissues are used.The frozen organs (e.g., liver or kidney) are thawed on ice and brieflyrinsed with PBS. The organs are homogenized in cold PBS using tissuegrinders followed by 3 cycles of freeze-thawing using liquid nitrogen.Tissue lysates are separated from the cellular debris and lipids. Thetissue lysates are diluted with PBS containing protease inhibitors,divided into 50 μL aliquots and heated at different temperatures.Soluble fractions are isolated and analyzed by western blot.

CETSA-Like Dot-Blot Experiments on Purified Proteins.

Purified protein (0.5 μg) is added to the wells of a PCR plate and thevolume adjusted to 50 μL by addition of buffer or cell lysates andligands depending on the experimental setup. The samples are heated forthe designated time and temperature in a thermocycler. After heating,the samples are immediately centrifuged for 15 min at 3000×g andfiltered using a 0.65 μm Multiscreen HTS 96 well filter plate. 3 μL ofeach filtrate are blotted onto a nitrocellulose membrane. Primaryantibody and secondary conjugate are used for immunoblotting. Allmembranes are blocked with blocking buffer; standard transfer andwestern blot protocols recommended by the manufacturers are used. Allantibodies are diluted in blocking buffer. The dot-blot is developed.Chemiluminescence intensities are detected and imaged. Raw dot blotimages are processed. The background is subtracted and intensities arequantified. Graphs are plotted and fitted using sigmoidal dose-response(variable slope).

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A compound of Formula VIII:

or a pharmaceutically acceptable salt thereof, wherein: H-VIII is anoptionally substituted pyrimidinyl, wherein ring carbons of H-VIII are,at each occurrence, independently optionally substituted with R², R¹⁴,or R¹⁶; L¹ is a bond or —NR⁵—; L² is —CH₂—; A is piperidinyl; m is aninteger from 0 to 9; B is B-II, wherein B is connected at any ring atomto L²; and B-II is

wherein Z¹ is CCH₃; Z² and Z⁸ are CH; Z⁵ is C; Z⁶ is NR⁹; and Z⁷ is CCN;n is an integer from 0 to 3; each of R², R⁵, R⁹, R¹⁴, and R¹⁶ is, ateach occurrence, independently selected from H, halo, hydroxyl, amino,cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl,alkenyl, alkynyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl,hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy,cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl,heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy,heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy,aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl,heteroaryloxy, heteroarylalkyloxy, heteroarylamino, andheteroarylalkylamino; R^(A) is, at each occurrence, independentlyselected from halo, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl,heterocyclylalkyl, and cycloalkylalkyl; and R^(B) is, at eachoccurrence, independently selected from halo, hydroxyl, amino, cyano,dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, alkenyl,alkynyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl,alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy,cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl,heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino,heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino,aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy,heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino.
 2. Thecompound of claim 1, wherein the compound is a compound of FormulaVIII-A:

or a pharmaceutically acceptable salt thereof, wherein: X¹ is CR², X² isN, X¹² is C, X¹⁴ is N, X¹³ is CR¹⁶, and X¹¹ is CR¹⁴; or X¹ is N, X² isCR², X¹² is C, and X¹⁴ is CR², X¹³ is N, and X¹¹ is CR¹⁴; or X¹ is CR²,X² is N, X¹² is C, X¹⁴ is CR², X¹³ is CR¹⁶, X¹¹ is N; L¹ is a bond or—NR⁵—; L² is —CH₂—; A is piperidinyl; m is an integer from 0 to 9; B isB-II, wherein B is connected at any ring atom to L²; and B-II is

wherein Z¹ is CCH₃; Z² and Z⁸ are CH; Z⁵ is C; Z⁶ is NR⁹; and Z⁷ is CCN;n is an integer from 0 to 3; each of R², R⁵, R⁹, R¹⁴, and R¹⁶ is, ateach occurrence, independently selected from H, halo, hydroxyl, amino,cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl,alkenyl, alkynyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl,hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy,cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl,heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy,heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy,aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl,heteroaryloxy, heteroarylalkyloxy, heteroarylamino, andheteroarylalkylamino; R^(A) is, at each occurrence, independentlyselected from halo, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl,heterocyclylalkyl, and cycloalkylalkyl; and R^(B) is, at eachoccurrence, independently selected from halo, hydroxyl, amino, cyano,dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, alkenyl,alkynyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl,alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy,cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl,heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino,heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino,aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy,heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino.
 3. Thecompound of claim 2, wherein: X¹ is CR²; X² is N; X¹¹ is N; X¹² is C;X¹³ is CR¹⁶; and X¹⁴ is CR².
 4. The compound of claim 2, wherein X¹⁴ isCR², wherein R² is aralkyl, aryloxy or arylamino, and wherein saidaralkyl, aryloxy and arylamino are substituted with one or moresubstituents selected from halo, alkyl, —C(═O)R_(g) and—C(═O)NR_(g)R_(h), wherein R_(g) and R_(h) are independently hydrogen oralkyl.
 5. The compound of claim 1, wherein A has one of the followingstructures:

wherein the H of any CH or NH may be replaced with a bond to L¹, L² orR^(A).
 6. The compound of claim 2, wherein the compound has thestructure of Formula VIII-B:

or Formula VIII-C:

or Formula VIII-D:

or Formula VIII-E:

or Formula VIII-F:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, wherein n is
 0. 8. The compound of claim 1, wherein R², R¹⁴, and R¹⁶,when present, are each independently H or haloalkyl.
 9. The compound ofclaim 1, wherein R⁹ is

wherein: G is selected from a bond, alkylene, heteroalkylene, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle, wherein G is optionallysubstituted with one or more R³² groups; V is absent or selected from aC₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle; wherein V isoptionally substituted with one or more R³² groups; each of R²¹ and R³²is, at each occurrence, independently selected from: H, halogen, —OR²⁰,—N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰,—S(O)₂R²⁰, —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰),—P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, and —CN; C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆alkynyl, each of which is independently optionallysubstituted at each occurrence with one or more substituents selectedfrom halogen, —OR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,—C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰,—NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN,C₃₋₁₀ carbocycle, and 3- to 10-membered heterocycle; and C₃₋₁₀carbocycle and 3- to 10-membered heterocycle; wherein two R³² on thesame carbon atom can come together to form a C₃₋₁₀ carbocycle or 3- to10-membered heterocycle; wherein each C₃₋₁₀ carbocycle and 3- to10-membered heterocycle of R³² is independently optionally substitutedwith one or more substituents selected from halogen, —OR²⁰, —SR²⁰,—N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰,—S(O)₂R²⁰, —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰),—P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl; R²⁰ at each occurrence is independently selected from:hydrogen; C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, —OR³⁰, —SR³⁰, —N(R³⁰)₂,—N(R³⁰)C(O)R³⁰, —C(O)R³⁰, —C(O)OR³⁰, —C(O)N(R³⁰)₂, —OC(O)R³⁰, —S(O)₂R³⁰,—S(O)₂N(R³⁰)₂, —N(R³⁰)S(O)₂R³⁰, —NO₂, —P(O)(OR³⁰)₂, —P(O)(R³⁰)₂,—OP(O)(OR³⁰)₂, and —CN; and 3- to 10-membered heterocycle and C₃₋₁₀carbocycle; and R³⁰ at each occurrence is independently selected fromhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.
 10. The compoundof claim 1, wherein B is B-II, and B-II is connected to L² at a positionselected from the group consisting of


11. A compound that is:

or a pharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 13. A method of inhibiting the interaction of meninand one or more of MLL1, MLL2, a MLL fusion protein, and a MLL PartialTandem Duplication, comprising contacting menin with an effective amountof a compound of claim
 1. 14. A method of treating a disease orcondition associated with MLL fusion proteins, comprising administeringto a subject in need thereof a therapeutically effective amount of acompound of claim 1, wherein the disease or condition comprises acutemyeloid leukemia or prostate cancer.